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. 2018 Sep 12;23(9):2333. doi: 10.3390/molecules23092333

Chemical Constituents from Croton Species and Their Biological Activities

Wen-Hui Xu 1, Wei-Yi Liu 1, Qian Liang 1,*
PMCID: PMC6225158  PMID: 30213129

Abstract

The genus Croton belongs to the Euphorbiaceae family, which comprises approximately 1300 species. Many Croton species have been used as folk medicines. This review focuses on the chemical constituents from Croton species and their relevant biological activities, covering the period from 2006 to 2018. A total of 399 new compounds, including 339 diterpenoids, were reported. Diterpenoids are characteristic components of the Croton species. These isolated compounds exhibited a broad spectrum of bioactivities, including cytotoxic, anti-inflammatory, antifungal, acetylcholinesterase inhibitory, and neurite outgrowth-promoting properties. The present review provides a significant clue for further research of the chemical constituents from the Croton species as potential medicines.

Keywords: Croton species, phytochemistry, biological activities, diterpenoids, cytotoxicity

1. Introduction

The genus Croton belongs to the Euphorbiaceae family, and contains approximately 1300 species of trees, shrubs, and herbs, which are widely distributed throughout tropical and subtropical regions of the world. Many Croton species have been used as folk medicines in Africa, south Asia, and south America, for the treatment of many diseases such as stomachache, abscesses, inflammation, and malaria [1,2,3]. The seeds of C. tiglium, which are well-known as “badou”, had been utilized as a traditional Chinese medicine to treat gastrointestinal disorders, intestinal inflammation, and rheumatism. The roots of C. crassifolius, known as “jiguxiang” in China, are mainly used as a traditional medicine for the treatment of stomachache and sore throat [3]. The genus Croton is abundant in diverse diterpenoids, including clerodane, tigliane, kaurane, labdane, cembrane, and pimarane, with a wide range of biological activities, such as cytotoxic, anti-inflammatory, and anti-microbial [1,2,3,4,5]. Due to their great structural diversity and broad relevant bioactivities, Croton species have attracted increasing research attention. Several authors have provided reviews about the chemical constituents and biological activities of Croton species. A review came out in 2006 regarding clerodane diterpenes isolated from Croton species, their 13C-NMR spectroscopic data, and biological activities [2]. In 2007, a comprehensive review on the traditional uses, chemistry, and pharmacology of Croton species was published [1]. In 2013, anticancer and antioxidant activities of extracts and pure compounds from several Croton species were reviewed [4]. Five review articles were published in recent years which focused on ethnopharmacological uses, phytochemistry, and pharmacology of a single Croton species [6,7,8,9,10]. In the last decade, there has been a dramatic progress in the chemical constituents and relevant biological activities of Croton species. However, so far, no comprehensive review has been published since 2007. In the present review, we summarize systematically the research advances on the new chemical constituents and their biological activities of Croton species reported in the literature, as found on Web of Science, Google Scholar, PubMed, and SciFinder, from 2006 to March 2018, with the aim of providing a basis for further research of natural product drug discovery.

2. Chemical Constituents

To date, 399 new compounds have been isolated and identified from Croton species, including 339 diterpenoids (1–339), seven sesquiterpenoids (340–346), one sesterterpenoid (347), one triterpenoid (348), 21 glycosides (349–369), eight alkaloids (370–377), three benzoate derivatives (378–380), three pyran-2-one derivatives (381–383), two cyclopeptide (384, 385), two tropone derivatives (386, 387), two limonoids (388, 389), and ten miscellaneous compounds (390–399). Their structures, molecular formula, names, corresponding sources, and references are summarized in Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9, Figure 10, Figure 11, Figure 12 and Figure 13 and Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12, Table 13, Table 14, Table 15, Table 16, Table 17, Table 18, Table 19, Table 20, Table 21, Table 22, Table 23, Table 24, Table 25, Table 26 and Table 27.

Figure 1.

Figure 1

Figure 1

Figure 1

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Clerodane type diterpenoids from the genus Croton.

Figure 2.

Figure 2

Figure 2

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Tigliane type diterpenoids from the genus Croton.

Figure 3.

Figure 3

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Kaurane type diterpenoids from the genus Croton 1.

Figure 4.

Figure 4

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Crotofolane type diterpenoids from the genus Croton.

Figure 5.

Figure 5

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Labdane type diterpenoids from the genus Croton.

Figure 6.

Figure 6

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Cembrane type diterpenoids from the genus Croton.

Figure 7.

Figure 7

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Abietane type diterpenoids from the genus Croton.

Figure 8.

Figure 8

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Casbane, Halimane, Pimarane and Cleistanthane type diterpenoids from the genus Croton.

Figure 9.

Figure 9

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Grayanane, Atisane, Phytane, Laevinane type diterpenoids and Meroditerpenoids from the genus Croton.

Figure 10.

Figure 10

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Sesquiterpenoids, Sesterterpenoid and Triterpenoid from the genus Croton.

Figure 11.

Figure 11

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Glycosides from the genus Croton.

Figure 12.

Figure 12

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Alkaloids from the genus Croton.

Figure 13.

Figure 13

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Miscellaneous compounds from the genus Croton.

Table 1.

Clerodane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
1 ent-3,13E-clerodadiene-15-formate C21H34O2 C. sylvaticus [12]
2 9-[2-(2(5H)-furanone-4-yl)ethyl]-4,8,9-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-4-carboxylic acid C20H28O4 C. crassifolius [14]
3 9-[2-(2(5H)-furanone-4-yl)ethyl]-4,8,9-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-4-carboxylic ester C21H30O4 C. crassifolius [14]
4 Centrafricine I C21H24O6 C. mayumbensis [19]
5 Marrubiagenin C20H28O4 C. glabellus [15]
6 Methyl 15,16-epoxy-3,13(16),14-ent-clerodatrien-18,19-olide-17-carboxylate C21H26O5 C. oblongifolius [29]
7 Dimethyl 15,16-epoxy-12-oxo-3,13(16),14-ent-clerodatriene-17,18-dicarboxylate C22H28O6 C. oblongifolius [29]
8 Isoteucvin C19H20O5 C. jatrophoides [30]
9 Jatrophoidin C21H22O7 C. jatrophoides [30]
10 8-Epicordatin C21H26O6 C. palanostigma [31]
11 laevigatbenzoate C27H31O5 C. laevigatus [13]
12 3,4,15,16-diepoxy-cleroda-13(16),14-diene-12,17-olide C20H26O4 C. oblongifolius [22]
13 Crassifolin A C21H30O4 C. crassifolius [16]
14 Crassifolin B C20H29O4 C. crassifolius [16]
15 Crassifolin C C21H24O5 C. crassifolius [16]
16 Crassifolin D C21H24O6 C. crassifolius [16]
17 Crassifolin E C20H23O6 C. crassifolius [16]
18 Crassifolin F C23H29O7 C. crassifolius [16]
19 Crassifolin G C19H20O6 C. crassifolius [16]
20 Methyl 3-oxo-12-epibarbascoate C21H26O6 C. urucurana [32]
21 Laevinoids A C20H22O5 C. laevigatus [20]
22 Laevinoids B C20H23O5Cl C. laevigatus [20]
23 Crotonolide A C20H18O6 C. laui [21]
24 Crotonolide B C21H24O6 C. laui [21]
25 Isocrotonolide B C21H24O6 C. laui [21]
26 Crotonolide C C23H26O8 C. laui [21]
27 Isocrotonolide C C23H26O8 C. laui [21]
28 Crotonolide D C21H26O6 C. laui [21]
29 Isocrotonolide D C21H26O6 C. laui [21]
30 Crotonolide E C20H26O4 C. laui [21]
31 Crotonolide F C20H26O4 C. laui [21]
32 Crotonolide G C20H32O C. laui [21]
33 Crotonolide H C20H32O4 C. laui [21]
34 12-Deoxycrotonolide H C20H32O3 C. laui [21]
35 Crotonoligaketone C23H26O8 C. oligandrum [33]
36 Crotonpene A C20H26O3 C. yanhuii [23]
37 Crotonpene B C21H28O5 C. yanhuii [23]
38 Crassifolin I C20H22O6 C. crassifolius [34]
39 Crassifolin H C19H20O5 C. crassifolius [34]
40 Crotoeurin A C38H36O1 C. euryphyllus [25]
41 Crotoeurin B C20H24O6 C. euryphyllus [25]
42 Crotoeurin C C20H22O6 C. euryphyllus [25]
43 3-Oxo-15,16-epoxy-4α,12-dihydroxy-ent-neo-clerodan-13(16),14-diene C20H30O4 C. limae [35]
44 15,16-Epoxy-3α,4α,12-trihydroxy-ent-neo-clerodan- 13(16),14-diene C20H32O4 C. limae [35]
45 3α,4α,15,16-Tetrahydroxy-ent-neo-cleroda-13E-ene C20H36O4 C. limae [35]
46 Cracroson A C19H21O6 C. crassifolius [26]
47 Cracroson B C20H22O6 C. crassifolius [26]
48 Cracroson C C19H19O4N C. crassifolius [26]
49 Crassifolin J C20H20O5 C. crassifolius [36]
60 Crotocorylifuran-2-one C22H24O8 C.megalocarpoides [27]
61 Megalocarpoidolide D C22H22O8 C.megalocarpoides [27]
62 7,8-Dehydrocrotocorylifuran C22H24O7 C.megalocarpoides [27]
63 Megalocarpoidolide E C22H24O8 C.megalocarpoides [27]
64 Megalocarpoidolide F C22H24O8 C.megalocarpoides [27]
65 Megalocarpoidolide G C22H24O9 C.megalocarpoides [27]
66 Megalocarpoidolide H C24H28O10 C.megalocarpoides [27]
67 Launine K C27H36O3 C. laui [37]
68 Crassin A C17H20O4 C. crassifolius [17]
69 Crassin B C17H20O4 C. crassifolius [17]
70 Crassin C C21H24O6 C. crassifolius [17]
71 Crassin D C20H20O5 C. crassifolius [17]
72 Crassin E C19H20O3 C. crassifolius [17]
73 Crassin F C19H18O7 C. crassifolius [17]
74 Crassin G C20H26O5 C. crassifolius [17]
75 Crassin H C21H30O5 C. crassifolius [17]
76 Crassifolius A C20H22O5 C. crassifolius [38]
77 Crassifolius B C21H24O6 C. crassifolius [38]
78 Crassifolius C C21H26O5 C. crassifolius [38]
79 Crolaevinoid C C27H28O6 C. laevigatus [39]
80 Crolaevinoid D C27H32O8 C. laevigatus [39]
81 Crolaevinoid E C20H28O6 C. laevigatus [39]
82 Crolaevinoid F C21H30O5 C. laevigatus [39]
83 Norcrassifolin C19H18O4 C. crassifolius [28]
84 Hypolein A C20H26O4 C. hypoleucus [24]
85 Hypolein B C20H28O3 C. hypoleucus [24]
86 Hypolein C C20H28O3 C. hypoleucus [24]
87 Cracroson E C19H20O6 C. crassifolius [40]
88 Cracroson F C19H20O6 C. crassifolius [40]
89 Cracroson G C21H26O7 C. crassifolius [40]
90 12-Epi-megalocarpoidolide D C22H22O8 C. oligandrus [18]
91 Crotonolins A C22H22O10 C. oligandrus [18]
92 Crotonolins B C22H22O10 C. oligandrus [18]
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Table 2.

Tigliane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
93 12-O-isobutyrylphorbol-13-decanoate C34H52O8 C. tiglium [45]
94 12-O-(2-methyl)butyrylphorbol-13-octanoate C33H50O8 C. tiglium [45]
95 12-O-[(2R)-N,N-dimethyl-3-methylbutanoyl]-4-deoxyphorbol 13-acetate C29H43NO7 C. ciliatoglandulifer [41]
96 12-O-[(2S)-N,N-dimethyl-3-methylbutanoyl]-4-deoxyphorbol 13-acetate C29H43NO7 C. ciliatoglandulifer [41]
97 12-O-[(2R)-N,N-Dimethyl-3-methylbutanoyl]phorbol 13-acetate C29H43NO8 C. ciliatoglandulifer [41]
98 12-O-[3-Methyl-2-butenoyl]-4-deoxyphorbol 13-acetate C27H36NO7 C. ciliatoglandulifer [41]
99 12-O-(2-methyl)butyrylphorbol-13-tiglate C30H42O8 C. tiglium [46]
100 12-O-tiglylphorbol-13-propionate C28H38O8 C. tiglium [46]
101 13-O-acetylphorbol-20-oleate C40H62O8 C. tiglium [46]
106 12-O-tiglyl-4-deoxy-4α-phorbol-13-(2-methyl)butyrate C30H42O7 C. tiglium [46]
107 Alienusolin C42H66O8 C. alienus [42]
108 12-O-acetyl-5,6-didehydro-7-oxophorbol-13-yl 2-methylbutanoate C27H36O9 C. tiglium [47]
109 12-O-acetyl-5,6-didehydro-7-oxophorbol-13-yl2-methylpropanoate C26H34O9 C. tiglium [47]
110 12-Oacetyl-5,6-didehydro-6,7-dihydro-7-hydroxyphorbol-13-yl 2-methylbutanoate C27H38O9 C. tiglium [47]
111 12-O-decanoyl-7-hydroperoxy-phorbol-5-ene-13-acetate C32H42O10 C. mauritianus [43]
112 20-deoxy-20-oxophorbol12-tiglate 13-(2-methyl)butyrate C30H40O8 C. tiglium [48]
113 12-O-acetylphorbol-13-isobutyrate C26H36O8 C. tiglium [48]
114 12-O-benzoylphorbol-13-(2-methyl)butyrate C32H40O8 C. tiglium [48]
115 12-O-tiglyl-7-oxo-5-ene-phorbol-13-(2-methyl)butyrate C30H40O9 C. tiglium [48]
116 13-O-(2-metyl)butyryl-4-deoxy-4a-phorbol C25H36O6 C. tiglium [48]
117 Crotignoid A C30H42O10 C. tiglium [49]
118 Crotignoid B C29H40O10 C. tiglium [49]
119 Crotignoid C C30H42O9 C. tiglium [49]
120 Crotignoid D C29H40O9 C. tiglium [49]
121 Crotignoid E C29H38O9 C. tiglium [49]
122 Crotignoid F C28H36O9 C. tiglium [49]
123 Crotignoid G C30H44O8 C. tiglium [49]
124 Crotignoid H C29H38O8 C. tiglium [49]
125 Crotignoid I C30H44O8 C. tiglium [49]
126 Crotignoid J C31H38O8 C. tiglium [49]
127 Crotignoid K C29H34O7 C. tiglium [49]
128 Crotusin A C36H54O10 C. caudatus [44]
129 Crotusin B C46H72O11 C. caudatus [44]
130 Crotusin C C36H52O11 C. caudatus [44]
131 12-O-tiglylphorbol-4-deoxy- 4β-phorbol-13-acetate C27H36O7 C. tiglium [50]
132 12-O-tiglylphorbol-4-deoxy-4β-phorbol-13-hexadecanoate C41H64O7 C. tiglium [50]
133 13-O-acetylphorbol-4-deoxy-4β-phorbol-20-oleate C40H62O7 C. tiglium [50]
134 13-O-acetylphorbol-4-deoxy-4β-phorbol-20-linoleate C40H60O7 C. tiglium [50]
135 4-deoxy-20-oxophorbol 12-tiglyl 13-acetate C27H34O7 C. tiglium [51]
136 7-oxo-5-ene-phorbol-13-(2-methylbutyrate) C25H34O8 C. tiglium [51]
137 7-hydroxyl-phorbol-5-ene-13-(2-methyl)butyrate C25H36O8 C. tiglium [51]
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Table 3.

Kaurane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
149 Caracasine C21H30O3 C. caracasana [53]
150 Caracasine acid C20H28O3 C. caracasana [53]
151 Kongensin A C22H30O5 C. kongensis [56]
152 Kongensin B C22H30O6 C. kongensis [56]
153 Kongensin C C20H28O5 C. kongensis [56]
154 Kongensin D C20H28O4 C. kongensis [57]
155 Kongensin E C26H36O7 C. kongensis [57]
156 Kongensin F C24H34O5 C. kongensis [58]
157 Crotonkinin A C20H30O2 C. tonkinensis [62]
158 Crotonkinin B C22H32O4 C. tonkinensis [62]
159 14-epi-hyalic acid C20H28O4 C. argyrophylloides [63]
160 14-[(2-methylbutanoyl)oxy]-3,4-seco-ent-kaura-4(19),16-dien-3-oic acid C25H39O4 C. megistocarpus [54]
161 14-{[(2Z)-2-methylbut-2-enoyl]oxy}-3,4-seco-ent-kaura-4(19),16-dien-3-oic acid C25H37O4 C. megistocarpus [54]
162 ent-11β-acetoxykaur-16-en-18-ol C22H34O3 C. tonkinensis [64]
163 ent-11α-hydroxy-18-acetoxykaur-16-ene C22H34O3 C. tonkinensis [64]
164 ent-14β-hydroxy-18-acetoxykaur-16-ene C22H34O3 C. tonkinensis [64]
165 ent-7α-hydroxy-18-acetoxykaur-16-ene C22H34O3 C. tonkinensis [64]
166 ent-14S*-hydroxykaur-16-en-19-oic acid C20H30O3 C. pseudopulchellus [65]
167 ent-14S*,17-dihydroxykaur-15-en-19-oic acid C20H30O4 C. pseudopulchellus [65]
168 ent-3,4-seco-17-oxo-kaur-4(19),15(16)-dien-3-oic acid C20H28O3 C. oblongifolius [55]
169 Crotonkinin C C22H30O5 C. tonkinensis [66]
170 Crotonkinin D C24H34O6 C. tonkinensis [66]
171 Crotonkinin E C24H34O5 C. tonkinensis [66]
172 Crotonkinin F C24H34O5 C. tonkinensis [66]
173 Crotonkinin G C23H36O5 C. tonkinensis [66]
174 Crotonkinin H C22H36O4 C. tonkinensis [66]
175 Crotonkinin I C24H36O5 C. tonkinensis [66]
176 Crotonkinin J C23H34O5 C. tonkinensis [66]
177 14β-hydroxy-3-oxo-ent-kaur-16-ene C20H30O2 C. kongensis [67]
178 Kongeniod A C21H30O3 C. kongensis [59]
179 Kongeniod B C21H30O4 C. kongensis [59]
180 Kongeniod C C23H32O5 C. kongensis [59]
181 15-oxo-17(10′-α-pinenyl)-kauran-18-oic acid C30H44O3 C. limae [35]
182 Micansinoic acid C40H58O7 C. micans [60]
183 Isomicansinoic acid C40H58O7 C. micans [60]
184 Dimethylester of micansinoic C42H62O7 C. micans [60]
185 Methyl-micansinoic acid C41H60O7 C. micans [60]
186 Ethyl-micansinoic acid C42H62O7 C. micans [60]
187 Crotonkinensin C C40H62O8 C. tonkinensis [61]
188 Crotonkinensin D C44H66O10 C. tonkinensis [61]
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Table 4.

Crotofolane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
189 Crotocascarin A C25H32O7 C. cascarilloides [68]
190 Crotocascarin B C25H32O7 C. cascarilloides [68]
191 Crotocascarin C C25H32O8 C. cascarilloides [68]
192 Crotocascarin D C25H32O6 C. cascarilloides [68]
193 Crotocascarin E C26H34O8 C. cascarilloides [68]
194 Crotocascarin F C24H30O7 C. cascarilloides [68]
195 Crotocascarin G C24H30O7 C. cascarilloides [68]
196 Crotocascarin H C24H30O8 C. cascarilloides [68]
197 Crotocascarin α C24H32O8 C. cascarilloides [68]
198 Crotocascarin β C24H32O7 C. cascarilloides [68]
199 (5β,6β)-5,6: 13,16-diepoxycrotofola-4(9),10(18),13,15-tetraen-1-one C20H22O3 C. argyrophyllus [72]
200 (5β,6β)-5,6: 13,16-diepoxy-2-epicrotofola-4(9),10(18),13,15-tetraen-1-one C20H22O3 C. argyrophyllus [72]
201 (5β,6β)-5,6: 13,16-diepoxy-16-hydroxycrotofola-4(9),10(18),13,15-tetraen-1-one C20H22O4 C. argyrophyllus [72]
202 (5β,6β)-5,6: 13,16-diepoxy-16-hydroxy-2-epi-crotofola-4(9),10(18),13,15-tetraen-1-one C20H22O4 C. argyrophyllus [72]
203 Crotocarasin A C20H22O4 C. caracasanus [73]
204 Crotocarasin B C20H22O4 C. caracasanus [73]
205 Crotocarasin C C22H26O5 C. caracasanus [73]
206 Crotocarasin D C22H26O5 C. caracasanus [73]
207 EBC-162 C20H24O2 C. insularis [74]
208 EBC-233 C20H24O4 C. insularis [74]
209 EBC-300 C20H24O4 C. insularis [74]
210 EBC-240 C20H26O5 C. insularis [74]
211 EBC-241 C20H26O5 C. insularis [74]
212 Crotocascarin I C20H24O5 C. cascarilloides [69]
213 Crotocascarin J C20H24O6 C. cascarilloides [69]
214 Crotocascarin K C20H24O5 C. cascarilloides [69]
215 Crotocascarin γ C19H24O6 C. cascarilloides [69]
216 Crotocascarin L C22H26O7 C. cascarilloides [70]
217 Crotocascarin M C21H26O6 C. cascarilloides [70]
218 Crotocascarin N C20H22O6 C. cascarilloides [70]
219 Crotocascarin O C25H34O9 C. cascarilloides [70]
220 Crotocascarin P C25H34O8 C. cascarilloides [70]
221 Crotocascarin Q C25H32O7 C. cascarilloides [70]
222 Neocrotocascarin C25H32O8 C. cascarilloides [70]
223 Crotodichogamoin A C20H22O4 C. dichogamus [75]
224 Crotodichogamoin B C20H22O2 C. dichogamus [75]
225 Cascarinoid A C28H31NO5 C. cascarilloides [71]
226 Cascarinoid B C28H31NO5 C. cascarilloides [71]
227 Cascarinoid C C28H31NO6 C. cascarilloides [71]
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Table 5.

Labdane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
228 Labdinine N C20H34O3 C. laui [76]
229 ent-12,15-dioxo-3,4-seco-4,8,13-labdatrien-3-oic acid C20H28O4 C. stipuliformis [78]
230 ent-12,15-epoxy-3,4-seco-4,8,12,14-labdatetraen-3-oic acid C20H28O3 C. stipuliformis [78]
231 ent-15-nor-14-oxo-3,4-seco-4,8,12(E)-labdatrien-3-oic acid C19H28O3 C. stipuliformis [78]
232 ent-12,15-dioxo-8,13-labdadien-3a-ol C20H28O3 C. stipuliformis [78]
233 Crotonlaevin A C18H30O4 C. laevigatus [79]
234 Crotonlaevin B C20H32O5 C. laevigatus [79]
235 Crotonlaevin C C21H34O5 C. laevigatus [79]
236 Crotonlaevin D C18H30O3 C. laevigatus [79]
237 Crotonlaevin E C20H32O5 C. laevigatus [79]
238 Crotonlaevin F C22H34O6 C. laevigatus [79]
239 Crotonlaevin G C22H36O5 C. laevigatus [79]
240 Crotonlaevin H C22H36O5 C. laevigatus [79]
241 Crotonlaevin I C20H34O4 C. laevigatus [79]
242 Crotonlaevin J C20H30O3 C. laevigatus [79]
243 Crotonlaevin K C20H28O3 C. laevigatus [79]
244 Crotonlaevin L C20H30O4 C. laevigatus [79]
245 Crotonlaevin M C20H30O4 C. laevigatus [79]
246 Crotonlaevin N C20H30O3 C. laevigatus [79]
247 Crotonlaevin O C20H30O3 C. laevigatus [79]
248 Crotonlaevin P C20H30O3 C. laevigatus [79]
249 Crotonolide I C20H34O3 C. laui [21]
250 Crotonolide J C19H30O3 C. laui [21]
251 Launine A C19H32O3 C. laui [82]
252 Launine B C19H32O4 C. laui [82]
253 Launine C C20H34O3 C. laui [82]
254 Launine D C20H34O3 C. laui [82]
255 Launine E C20H32O5 C. laui [82]
256 Launine F C20H32O5 C. laui [82]
257 Launine G C20H30O4 C. laui [82]
258 Launine H C20H30O4 C. laui [82]
259 Launine I C20H34O3 C. laui [82]
260 15,16-epoxy-4-hydroxy-labda-13(16),14-dien-3,12-dione C20H28O4 C. jacobinensis [77]
261 Crotondecalvatin A C29H42O4 C. decalvatus [80]
262 Crotondecalvatin B C30H42O6 C. decalvatus [80]
263 Bicrotonol A C40H68O4 C. crassifolius [81]
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Table 6.

Cembrane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
264 Launine O C20H34O2 C. laui [76]
265 Launine P C21H36O2 C. laui [76]
266 Furanocembranoid 1 C20H30O2 C. oblongifolius [83]
267 Furanocembranoid 2 C20H30O3 C. oblongifolius [83]
268 Furanocembranoid 3 C20H32O4 C. oblongifolius [83]
269 Furanocembranoid 4 C20H32O5 C. oblongifolius [83]
270 Laevigatlactone A C20H30O3 C. laeVigatus [84]
271 Laevigatlactone C C20H30O3 C. laeVigatus [84]
272 Laevigatlactone B C20H30O3 C. laeVigatus [84]
273 Laevigatlactone D C20H30O3 C. laeVigatus [84]
274 Laevigatlactone E C20H30O4 C. laeVigatus [84]
275 Laevigatlactone F C20H30O5 C. laeVigatus [84]
276 (+)-[1R*,2S*,7S*,8S*,12R*]-7,8-Epoxy-2,12-cyclocembra-3E,10Zdien-20,10-olide C20H28O3 C. gratissimus [85]
277 (+)-[1R*,10R*]-Cembra-2E,4E,7E,11Z-tetraen-20,10-olide C20H28O2 C. gratissimus [85]
278 (+)-[1R*,4S*,10R*]-4-Hydroxycembra-2E,7E,11Z-trien-20,10-olide C20H30O3 C. gratissimus [85]
279 (−)-[1R*,4R*,10R*]-4-Hydroxycembra-2E,7E,11Z-trien-20,10-olide C20H30O3 C. gratissimus [85]
280 (−)-(1R*,4R*,10R*)-4-Methoxycembra-2E,7E,11Z-trien-20,10-olide C21H32O3 C. gratissimus [86]
281 (−)-(1S*,4R*,10R*)-1-Hydroxy-4-methoxycembra-2E,7E,11Ztrien-20,10-olide C21H32O4 C. gratissimus [86]
282 (−)-(1S*,4S*,10R*)-1,4-Dihydroxycembra-2E,7E,11Z-trien-20,10-olide C20H30O4 C. gratissimus [86]
283 (−)-(1S*,4S*,10R*)-1,4-Dihydroxycembra-2E,7E,11Z-trien-20,10-olide C20H30O4 C. gratissimus [86]
284 (+)-(10R*)-Cembra-1E,3E,7E,11Z,16-pentaen-20,10-olide C20H26O C. gratissimus [86]
285 (+)-(10R*)-Cembra-1Z,3Z,7E,11Z,15-pentaen-20,10-olide C20H26O C. gratissimus [86]
286 (+)-(5R*,10R*)-5-Methoxycembra-1E,3E,7E,11Z,15-pentaen-20,10-olide C21H30O3 C. gratissimus [86]
287 (+)-(1S*,4S*,7R*,10R*)-1,4,7-Trihydroxycembra-2E,8(19),11Z-trien-20,10-olide C20H30O5 C. gratissimus [86]
288 (−)-(1S*,4S*,7S*,10R*)-1,4,7-Trihydroxycembra-2E,8(19),11Z-trien-20,10-olide C20H30O3 C. gratissimus [86]
289 (+)-(1S*,4R*,8S*,10R*)-1,4,8-Trihydroxycembra-2E,6E,11Z-trien-20,10-olide C20H30O5 C. gratissimus [86]
290 Cembranoid 1 C20H30O4 C. longissimus [87]
291 Cembranoid 2 C20H30O3 C. longissimus [87]
281 (−)-(1S*,4R*,10R*)-1-Hydroxy-4-methoxycembra-2E,7E,11Ztrien-20,10-olide C21H32O4 C. gratissimus [86]
282 (−)-(1S*,4S*,10R*)-1,4-Dihydroxycembra-2E,7E,11Z-trien-20,10-olide C20H30O4 C. gratissimus [86]
283 (−)-(1S*,4S*,10R*)-1,4-Dihydroxycembra-2E,7E,11Z-trien-20,10-olide C20H30O4 C. gratissimus [86]
284 (+)-(10R*)-Cembra-1E,3E,7E,11Z,16-pentaen-20,10-olide C20H26O C. gratissimus [86]
285 (+)-(10R*)-Cembra-1Z,3Z,7E,11Z,15-pentaen-20,10-olide C20H26O C. gratissimus [86]
286 (+)-(5R*,10R*)-5-Methoxycembra-1E,3E,7E,11Z,15-pentaen-20,10-olide C21H30O3 C. gratissimus [86]
287 (+)-(1S*,4S*,7R*,10R*)-1,4,7-Trihydroxycembra-2E,8(19),11Z-trien-20,10-olide C20H30O5 C. gratissimus [86]
288 (−)-(1S*,4S*,7S*,10R*)-1,4,7-Trihydroxycembra-2E,8(19),11Z-trien-20,10-olide C20H30O3 C. gratissimus [86]
289 (+)-(1S*,4R*,8S*,10R*)-1,4,8-Trihydroxycembra-2E,6E,11Z-trien-20,10-olide C20H30O5 C. gratissimus [86]
290 Cembranoid 1 C20H30O4 C. longissimus [87]
291 Cembranoid 2 C20H30O3 C. longissimus [87]
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Table 7.

Abietane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
292 Isolophanthin E C20H30O3 C. megalocarpoides [27]
293 rel-(1R,4aR,5R,8R)-methyl-7-(1-(methoxycarbonyl)vinyl)-5,8-diacetoxy-1,2,3,4a,5,6,7,8,9,10,10a-dodecahydro-1,4a-dimethyl-2-oxophenanthrene-1-carboxylate C26H34O9 C. argyrophylloides [63]
294 Crotontomentosin A C20H26O2 C. caudatus [88]
295 Crotontomentosin B C20H30O3 C. caudatus [88]
296 Crotontomentosin D C20H24O2 C. caudatus [88]
297 Crotontomentosin C C20H28O2 C. caudatus [88]
298 Crotontomentosin E C22H32O3 C. caudatus [88]
299 Crotolaevigatone A C20H24O3 C. laevigatus [89]
300 Crotolaevigatone B C20H26O2 C. laevigatus [89]
301 Crotolaevigatone C C20H26O3 C. laevigatus [89]
302 Crotolaevigatone D C20H28O4 C. laevigatus [89]
303 Crotolaevigatone E C19H24O2 C. laevigatus [89]
304 Crotolaevigatone F C20H30O4 C. laevigatus [89]
305 Crotolaevigatone G C20H30O4 C. laevigatus [89]
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Table 8.

Casbane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
306 1,4-dihydroxy-2E,6E,12E-trien-5-one-casbane C20H30O3 C. nepetaefolius [90]
307 4-hydroxy-2E,6E,12E-5-one-casbane C20H29O3 C. nepetaefolius [90]
308 1-hydroxy-(2E,6Z,12E)-casba-2,6,12-triene-4,5-dione C20H28O3 C. argyrophyllus [91]
309 6E,12E-casba-1,3,6,12-tetraen-1,4-epoxy-5-one C20H26O2 C. argyrophyllus [91]
310 (2E,5β,6E,12E)-5-hydroxycasba-2,6,12-trien-4-one C20H30O2 C. argyrophyllus [72]
311 EBC-324 C20H28O5 C. insularis [92]
312 EBC-329 C20H26O4 C. insularis [92]
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Table 9.

Halimane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
313 Crassifoliusin A C21H24O5 C. crassifolius [95]
314 Crotontomentosin F C21H30O3 C. caudatus [88]
315 Crolaevinoid A C27H30O7 C. laevigatus [39]
316 Crolaevinoid B C20H26O4 C. laevigatus [39]
317 Crothalimene A C20H26O4 C. dichogamus [75]
318 Crothalimene B C20H30O2 C. dichogamus [75]
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Table 10.

Pimarane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
319 ent-3β-hydroxypimara-8(14),9,15-trien-12-one C20H28O2 C. insularis [98]
320 EBC-316 C20H26O2 C. insularis [99]
321 EBC-325 C20H26O4 C. insularis [99]
322 EBC-326 C20H26O4 C. insularis [99]
323 EBC-327 C20H24O3 C. insularis [99]
324 EBC-345 C20H30O4 C. insularis [99]
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Table 11.

Cleistanthane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
325 3-hydroxycleistantha-13(17),15-diene C20H32O C. oblongifolius [93]
326 3,4-seco-cleistantha-4(18),13(17),15-trien-3-oic acid C20H30O2 C. oblongifolius [93]
327 rel-(5β,8α,10α)-8-hydroxy-13-methylpodocarpa-9(11),13-diene-3,12-dione C18H25O3 C. regelianus [94]
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Table 12.

Grayanane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
328 Crotonkinensin A C20H24O4 C. tonkinensis [100]
329 Crotonkinensin B C20H26O3 C. tonkinensis [100]
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Table 13.

Atisane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
330 Crotobarin C22H28O5 C. barorum [101]
331 Crotogoudin C20H26O3 C. goudotii [101]
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Table 14.

Phytane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
332 Launine L C20H32O3 C. laui [37]
333 Launine M C20H32O2 C. laui [37]
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Table 15.

Laevinane type diterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
334 Crolaevinoid G C20H24O6 C. laevigatus [39]
335 Crolaevinoid H C21H26O6 C. laevigatus [39]
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Table 16.

Meroditerpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
336 Steenkrotin A C20H24O6 C. steenkampianus [102]
337 Steenkrotin B C20H28O7 C. steenkampianus [102]
338 Norcrassin A C17H22O7 C. crassifolius [81]
339 Cracroson D C21H26O6 C. crassifolius [40]
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Table 17.

Sesquiterpenoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
340 6α -methoxy-cyperene C16H26O C. muscicarpa [103]
341 rel-(1R,4S,6R,7S,8αR)-decahydro-1-(hydroxymethyl)-4,9,9-trimethyl-4,7-(epoxymethano)azulen-6-ol C15H26O3 C. regelianus [94]
342 Blumenol A C13H20O3 C. pedicellatus [104]
343 Crocrassins A C15H24O3 C. crassifolius [105]
344 Crocrassins B C16H26O3 C. crassifolius [105]
345 1,3,5-cadinatriene-(7R,10S)-diol C15H25O2 C. dichogamus [75]
346 Cracroson H C15H22O3 C. crassifolius [40]
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Table 18.

Sesterterpenoid from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
347 Pseudopulchellol C25H40O C.pseudopulchellus [106]
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Table 19.

Triterpenoid from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
348 3α-hydroxy-urs-12,15-dien C30H48O C. bonplandianum [107]
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Table 20.

Glycosides from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
349 Cyperenoic acid-9-O-β-d-glucopyranoside C21H32O8 C. crassifolius [108]
350 3-O-β-d-xylopyranosylspathodic acid C35H56O9 C. lachnocarpus [109]
351 Helichrysoside-3′-methylether C31H28O14 C. zambesicus [110]
352 Crotonionoside A C29H42O11 C. cascarilloides [111]
353 Crotonionoside B C30H44O12 C. cascarilloides [111]
354 Crotonionoside C C24H42O12 C. cascarilloides [111]
355 Crotonionoside D C31H46O14 C. cascarilloides [111]
356 Crotonionoside E C35H52O16 C. cascarilloides [111]
357 Crotonionoside F C24H42O11 C. cascarilloides [111]
358 Crotonionoside G C29H40O11 C. cascarilloides [111]
359 Oblongionoside A C24H42O12 C. oblongifolius [112]
360 Oblongionoside B C24H42O12 C. oblongifolius [112]
361 Oblongionoside C C24H44O11 C. oblongifolius [112]
362 Oblongionoside D C24H44O11 C. oblongifolius [112]
363 Oblongionoside E C19H36O8 C. oblongifolius [112]
364 Oblongionoside F C19H36O8 C. oblongifolius [112]
365 Blumenol A glucoside C19H30O8 C. pedicellatus [10]
366 Sparsioside C53H102O10 C. sparsiorus [113]
367 3,12-dioxo-15,16-epoxy-4α-hydroxy-6-(β-glucopyranosyl)-ent-neo-clerodan-13(16),14-diene C26H38O10 C. limae [35]
368 Isocrotofolane glucoside C26H38O9 C. cascarilloides [69]
369 2-methoxyphenol-β-d-(6-O-β-d-apiofuranosyl) glucopyranoside C18H26O11 C. cascarilloides [69]
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Table 21.

Alkaloids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
370 Crotamide A C36H65NO C. sparsiflorus [114]
371 Crotamide B C38H69NO C. sparsiflorus [114]
372 Crotonine C12H14N2O4 C. tiglium [97]
373 Crotonimide A C16H20N2O3 C. pullei [115]
374 Crotsparsidine C17H17O3N C. sparsiflorus [96]
375 Crotonimide C. C20H20N2O3 C. alienus [42]
376 6-Hydroxy-1-methyl-2-dimethyl-3,4-tetrahydro-b-carbo-line C14H19N2O C. heliotropiifolius [116]
377 N-trans-feruloyl-3,5-dihydroxyindolin-2-one C20H20N2O6 C. echioides [117]
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Table 22.

Benzoate derivatives from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
378 2′-(3′’,4′’-dihydroxyphenyl)-ethyl-4-hydroxybenzoate C15H14O5 C. sylvaticus [118]
379 3-(4-hydroxy-3,5-dimethoxyphenyl)-propyl benzoate C18H20O5 C. hutchinsonianus [119]
380 3-(4-hydroxyphenyl)-propyl benzoate C16H16O3 C. hutchinsonianus [119]
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Table 23.

Pyran-2-one derivatives from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
381 Crotonpyrone A C17H28O3 C. crassifolius [120]
382 Crotonpyrone B C17H26O3 C. crassifolius [120]
383 Crotonpyrone C C19H28O3 C. crassifolius [121]
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Table 24.

Cyclicpeptides from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
384 Crotogossamide C37H56N10O11 C. gossypifolius [122]
385 [1−9-NαC]-crourorb A1 C37H56N10O11 C. urucurana [123]
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Table 25.

Tropone derivatives from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
386 Crototropone C10H12O4 C. zehntneri [124]
387 Pernambucone C15H18O2 C. argyroglossum [125]
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Table 26.

Limonoids from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
388 Musidunin C31H38O11 C. jatrophoides [126]
389 Musiduol C30H38O10 C. jatrophoides [126]
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Table 27.

Miscellaneous compounds from the genus Croton.

No. Compound Name Molecular Formula Sources Ref
390 Crotoncaudatin C22H22O9 C. caudatus [127]
391 8S-(−)-8-(4-hydroxy-3-methoxybenzoyl)-dihydrofuran-8(8′H)-one C20H30O2 C. kongensis [67]
392 Lobaceride C35H58O6 C. lobatus [129]
393 Laevifolin A C29H38O4 C. laevifolius [128]
394 Laevifolin B C29H38O4 C. laevifolius [128]
395 2,6-Dimethyl-1-oxo-4-indanecarboxylic acid C12H12O3 C. steenkampianus [102]
396 3(3′-Methoxy-5′-phenylfuran-2′-yl)propan-1-ol C14H16O3 C. oblongifolius [22]
397 Sparsifol C7H15O6 C. sparsiflorus [96]
398 Sparsioamide C43H81NO5 C. sparsiflorus [113]
399 hexyl Z-ferulate C16H22O4 C. laevigatus [89]
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2.1. Diterpenoids

Phytochemical investigations on Croton species revealed the predominant secondary metabolites as diterpenoids, including clerodane, tigliane, kaurane, crotofolane, labdane, cembrane, abietane, casbane, halimane, pimarane, cleistanthane, grayanane, atisane, phytane, and laevinane diterpenoids. Three hundred & thirty-nine new diterpenoids (1–339) were reported from Croton species.

2.1.1. Clerodanes

Ninety-two new clerodane diterpenoids (1–92) were isolated from Croton species, including two clerodane diterpenoid with acyclic at C-9s, eight clerodane diterpenoids with butenolide at C-9, and 82 furan-clerodane diterpenoids [11]. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 1 and Table 1. Two new clerodane diterpenoids with acyclic side chain at C-9, ent-3,13E-clerodadiene-15-formate (1) and 3α,4α,15,16-tetrahydroxy-ent-neo-cleroda-13E-ene (45), were isolated from the roots of C. sylvaticus [12] and the roots of C. limae [13], respectively. Eight new clerodane diterpenoids with butenolide at C-9 (2, 3, 5, 13, 14, 75, 91, 92) were obtained from three Croton species (C. crassifolius, C. glabellus, and C. oligandrus) [14,15,16,17,18]. Furan-clerodane diterpenoids are abundant in Croton species, and 82 new ones were isolated from different Croton species. For example, Centrafricine I (4) from C. mayumbensis was a new furan-clerodane diterpenoid with a 6, 18-γ-lactone ring [19]. Two novel rearranged ent-clerodane diterpenoids Laevinoids A, B (21, 22) containing an unusual 3/5 bicyclic ring were obtained from the branches and leaves of C. laevigatus; 22 represents the first chlorinated example of the clerodane family [20]. Compounds (23–27) bearing a C-19/C-20 six-membered ring were identified from C. laui [21]. Phytochemical investigations on three Croton species (C. oblongifolius, C. yanhuii, and C. hypoleucus) afforded six new furan-clerodanoids (12, 36, 37, 84–86) with a 3,4-epoxy moiety [22,23,24]. Crotoeurins A–C (40–42) were found from the twigs and leaves of C. euryphyllus. Among them, crotoeurin A (40) was a nor-clerodane diterpenoid dimer with a unique cyclobutane ring via a [2 + 2] cycloaddition [25]. Three new furan-clerodane diterpenoids, cracroson A–C (46–48) were obtained from C. crassifolius, while cracroson C (48) represents the first example of a clerodane diterpenoid alkaloid [26]. Twelve new ent-clerodanoids (55, 66) were isolated from the roots of C. megalocarpoides. Among them, compounds (58–66) possessed 9, 12-γ-lactone ring [27]. Investigation on the roots of C. crassifolius afforded eight new clerodanoids, crassins A−H (68–75). Among them, crassins A–B (68, 69) represents ring B rearranged clerodanoids, whereas crassins C (70) was ring A rearranged one [17]. One new nor-clerodane diterpenoid, norcrassifolin (83), with a 1,12-lactone six-membered ring, was isolated from C. crassifolius [28].

2.1.2. Tiglianes

Fifty-six new tigliane diterpenoids (93–148) were reported from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 2 and Table 2. Investigations on the aerial parts of C. ciliatoglandulifer produced four new tiglianoids (95–98). Among them, tiglianoids (95–97) possess a N,N-dimethyl moiety at 2′position [41]. Alienusolin (107) and compound (111) were obtained from the roots and the leaves of C. alienus and the leaves of C. mauritianus, respectively [42,43]. The twigs and leaves of C. caudatus produced three new tiglianoids, crotusins A–C (128–130) [44]. Tigliane diterpenoids were abundant in C. tiglium, other 47 new ones (93, 94, 99–106, 108–110, 112–127, 131–148) were isolated from C. tiglium [45,46,47,48,49,50,51,52]. Among them, compound (112) was the first tiglianoid with the C20-aldehyde group [48].

2.1.3. Kauranes

Fourty new kaurane diterpenoids (149–188) were found from Croton species. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 3 and Table 3. Five new 3,4-seco ent-kauranes (149–150, 160–161, 168) were isolated from C. caracasana [53], C. megistocarpus [54], and C. oblongifolius [55], respectively. Investigations on C. kongensis afforded eight new 8,9-seco-ent-kaurane diterpenes (151–154, 156, 178–180) [56,57,58,59]. Compound 181, one new kaurane bearing a monoterpene unit at C-16, was found from C. limae [35]. From the stems of C. micans, five new 3,4-seco-ent-kaurene dimers (182–186) were isolated [60], while other two dimeric ent-kaurane diterpenoids (187–188) were elucidated from C. tonkinensis [61].

2.1.4. Crotofolanes

Thirty-nine new crotofolane diterpenoids (189–227) were obtained from Croton species. Their structures, molecular formula, names, corresponding sources, and references are summarized in Figure 4 and Table 4. Twenty-four new crotofolane diterpenoids (189–198, 212–222, 225–227) were isolated from C. caracasanus [68,69,70,71]. Among them, three new crotofolane diterpenoid alkaloids, cascarinoids A–C (225–227), were firstly found. Investigations on C. argyrophyllus gave four new crotofolanes (199–202) [72]. Crotocarasin A–D (203–206) were isolated from the stems of C. caracasanus [73]. Five new 1, 14-seco-crotofolanes from C. insularis were obtained [74], while C. dichogamus yielded crotodichogamoin A–B (223–224) [75].

2.1.5. Labdanes

Thirty-six new labdane diterpenoids (228–263) were isolated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 5 and Table 5 12 new labdanes (228, 249–259) were isolated from C. laui [21,76,77]. From the leaves of C. stipuliformis, three 3,4-seco-ent-labdanes (229–231) and one ent-labdane (232) were obtained [78]. Investigation of C. laevigatus led to the isolation of 16 new labdanes (233–248). Among them, crotonlaevins A–B (233, 234), represents rare labdanes with a dodecahydronaphtho [1,2-c] furan moiety [79]. Three new labdane diterpenoids (260–262) were found from C. jacobinensis [77] and C. decalvatus [80], respectively. Bicrotonol A (263), one dimeric labdane-type diterpenoid, was obtained from the roots of C. crassifolius [81].

2.1.6. Cembranes

A total of 28 new cembrane diterpenoids (264–291) were obtained from Croton species. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 6 and Table 6. launine O-P (264, 265), two new cembranes, were reported from the aerial parts of C. laui [76]. Investigations on the stem bark of C. oblongifolius afforded four new furanocembranoids (266–269) [83]. laevigatlactones A–F (270–275), six new cembranoids possessing a rare six-membered lactone moiety attached to C-1 and C-20, were firstly isolated from C. laevigatus [84]. 14 new cembranoids (276–289) were found from C. gratissimus [85,86]. Among them, compound 276 was first example of a 2,12-cyclocembranolide. The leaves of C. longissimus produced two new cembranes (290, 291) [87].

2.1.7. Abietanes

Fourteen new abietane diterpenoids (292–305) were isolated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 7 and Table 7. Two new abietanes (292, 293) were obtained from C. megalocarpoides [27], and C. argyrophylloides [63], respectively. Investigation of C. caudatus led to the isolation of 5 new abietanes (294–298). Among them, crotontomentosin A (294) was a 9,10-seco abietane [88]. Crotolaevigatones A–G (299–305), 7 new abietanes were found from the twigs and leaves of C. laevigatus, and compounds (304, 305) possessed a 9,13-epidioxy moiety [89].

2.1.8. Casbanes

Seven new casbane diterpenoids (306–312) were found from Croton species. Their structures, molecular formula, names, corresponding sources, and references are summarized in Figure 8 and Table 8. Five new casbane s (306–310) were reported from C. nepetaefolius [90], and C. argyrophyllus [72,91], respectively. Investigations on the stem bark of C. insularis afforded two new casbanes, EBC-324 (311) and EBC-329 (312). Among them, EBC-329 (312) represented the first natural seco-casbane diterpene, while EBC-324 (311) was the first endoperoxide casbane [92].

2.1.9. Halimanes

Six new halimane diterpenoids (313–318) were reported from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 8 and Table 9. Investigations on the stem bark of C. oblongifolius afforded two new cleistanthanes (325, 326). Among them, compound 326 was a 3,4-seco cleistanthane [93]. One new bis-nor-cleistanthane diterpenoid (327), was found from the twigs and leaves of C. caudatus [94].

2.1.10. Pimaranes

Six new pimarane diterpenoids (319–324) were obtained from Croton species. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 8 and Table 10. All six new pimaranes (319–324) were isolated from C. insularis [96,97]. Among them, compound 319 was an important biosynthetic intermediate.

2.1.11. Cleistanthanes

Three new cleistanthane diterpenoids (325–327) were ioslated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 8 and Table 11. Investigations on the stem bark of C. oblongifolius afforded two new cleistanthanes (325, 326). Among them, compound 326 was a 3,4-seco cleistanthane [93]. One new bis-nor-cleistanthane diterpenoid (327), was found from the twigs and leaves of C. caudatus [94].

2.1.12. Grayananes, Atisanes, Phytanes, Laevinanes and Meroditerpenoids

From the leaves of C. tonkinensis, two new rare grayanane diterpenoids, crotonkinensins A (328) and B (329), were isolated [100]. Two new 3,4-seco atisane diterpenoids, crotobarin (330) from C. barorum and crotogoudin (331) from C. goudotii, were found [101]. Investigations on the aerial parts of C. laui gave two new phytane diterpenoids (332, 333) [37]. Two new laevinane diterpenoids, crolaevinoid G (334) and H (335), were obtained [39]. Two new meroditerpenoids, steenkrotin A (336) and B (337), containing new carbon skeletons, were isolated from the leaves of C. steenkampianus [102]. From the the roots of C. crassifolius, two new meroditerpenoids, norcrassin A (338) and cracroson D (339), were reported [35,69]. Among them, norcrassin A (338) possessing a new carbon skeleton with a 5/5/5/6 tetracyclic system, was a C16 tetranorditerpenoid, while cracroson D (339) featured a new skeleton with a rare cyclobutane ring. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 9 and Table 12, Table 13, Table 14, Table 15 and Table 16.

2.2. Sesquiterpenoids, Sesterterpenoids and Triterpenoids

Seven new sesquiterpenoids (340–346), one sesterterpenoid (347) and one triterpenoid (348) were ioslated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are summarized in Figure 10 and Table 17, Table 18 and Table 19. From C. muscicarpa, one new patchoulane sesquiterpenoid (340) was obtained [103]. A guaiane sesquiterpenoid (341) was isolated from C. regelianus [94]. Investigations on the leaves of C. pedicellatus afforded a bis-nor-sesquiterpenoid (342) [104]. Two rare sesquiterpenoid, Crocrassins A (343) and B (344) having cyclopropylcyclopentane moiety, were reported [105]. Other two sesquiterpenoids, 1,3,5-cadinatriene-(7R,10S)-diol (345) and cracroson H (346) were found from C. dichogamus [75], and C. crassifolius [40], respectively. One rare sesterterpenoid, pseudopulchellol (347), was isolated from the leaves of C. pseudopulchellus [106]. From the root of C. bonplandianum, a new ursane triterpenoid (348) was obtained [107].

2.3. Glycosides

Twenty-one new glycosides (349–369) were ioslated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 11 and Table 20. From C. crassifolius, a patchoulane sesquiterpenoid glycoside (349), an isocrotofolane glucoside (368), and a phenolic glycoside (369) were reported [69,108]. Compound 350, isolated from C. lachnocarpus, was the first triterpenoid glucoside reported from the genus Croton [109]. A new flavone glucoside (351) was found from the leaves of C. zambesicus [110]. Investigations on the leaves of C. cascarilloides and C. oblongifolius afforded 13 new megastigmane glycosides, crotonionosides A–G (352–358) and Oblongionosides A–F (359–364) [111,112]. One new bis-nor-sesquiterpenoid glycoside (365) was isolated from C. pedicellatus [104]. One new diglyceride galactoside (366) and one new clerodane glucoside (367) were obtained from C. sparsiorus [113], and C. limae [35], respectively.

2.4. Alkaloids

Eight new alkaloids (370–377) were reported from Croton species. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 12 and Table 21. From C. sparsiflorus, two new amide alkaloids crotamides A (370) and B (371), and one new proaporphine alkaloid, crotsparsidine (374) were isolated [96,114]. One new pyrazine derivative, crotonine (372) was obtained from the leaves of C. tiglium [97]. Investigations on C. cascarilloides afforded a new glutarimide alkaloid, crotonimide C (375) [42]. Other three new alkaloids (373, 376–377) were found from C. pullei, C. heliotropiifolius, and C. echioides, respectively [115,116,117].

2.5. Benzoate Derivatives, Pyran-2-One Derivatives, Cyclicpeptides, Tropone Derivatives and Limonoids

Three benzoate derivatives (378–380) were isolated from C. sylvaticus and C. hutchinsonianus [118,119]. Investigations on C. crassifolius afforded three new pyran-2-one derivatives, crotonpyrone A (381), B (382) and C (383) [120,121]. Two cyclicpeptides (384, 385) were obtained from C. gossypifolius and C. urucurana [122,123], while two tropone derivatives (386, 387) were isolated from C. zehntneri and C. argyroglossum [124,125]. From the root bark of C. jatrophoides, two new limonoids, musidunin (388) and musiduol (389), were found [126]. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 13 and Table 22, Table 23, Table 24, Table 25 and Table 26.

2.6. Miscellaneous Compounds

Flavonoids, lignans, and other types of 10 compounds were also isolated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 13 and Table 27. From the stems of C. caudatus, one new flavone, crotoncaudatin (390), was isolated [127]. A new nor-lignan (391) was obtained from the twigs and leaves of C. kongensis [67]. Investigations on C. laevifolius gave two new prenylated dihydrostilbenes, laevifolin A (393), B (394) and one new aromatic compound (399) [89,128]. A long chain linear ester, lobaceride (392) was isolated from the twigs and leaves of C. lobatus [129]. One indanone derivative (395) was found from the leaves of C. steenkampianus [102], while a trisubstituted furan derivative (396) was isolated from the bark of C. oblongifolius [22]. From C. sparsiflorus, an inositol, sparsifol (397), and a sphingolipid, sparsioamide (398), were obtained [96,113].

3. Biological Activities

Compounds isolated from Croton species exert a wide range of biological activities, including cytotoxic, anti-inflammatory, antifungal, acetylcholinesterase inhibitory, and neurite outgrowth-promoting activities.

3.1. Cytotoxic Activity

The anti-tumor activity of many plants from the Croton species have been reported. Therefore, the cytotoxicity of the isolated compounds is the most commonly studied bioactivity. The cytotoxic activities of the isolated compounds from the Croton species are listed in Table 28. Four new tigliane diterpene esters (135–137, 139) from the leaves of C. tiglium, exhibited most potent cytotoxic activity against K562 cell line with IC50 values of 0.03, 0.03, 0.07 and 0.05 μM, respectively [51].

Table 28.

Cytotoxic activity of compounds from the genus Croton.

Compounds Tumor Cell Line Activity (IC50) Ref
Methyl 15,16-epoxy-3,13(16),14-ent-clerodatrien-18,19-olide-17-carboxylate (6) HuCCA-1 36.0 μg/mL [29]
KB 26.0 μg/mL [29]
HeLa 30.0 μg/mL [29]
MDA-MB231 29.0 μg/mL [29]
T47D 10.0 μg/mL [29]
Dimethyl-15,16-epoxy-12-oxo-3,13 (16)14-ent-clerodatriene-17,18-dicarboxylate (7) HuCCA-1 39.0 μg/mL [29]
KB 27.0 μg/mL [29]
HeLa 29.0 μg/mL [29]
MDA-MB231 27.0 μg/mL [29]
T47D 25.0 μg/mL [29]
Laevigatbenzoate (8) HeLa 45.4 μM [13]
Crotonolide A (23) HL-60 9.42 μM [21]
P-388 7.45 μM [21]
15-oxo-17(10′-α-pinenyl)-kauran-18-oic acid (181) HCT-116 7.14 μg/mL [35]
OVCAR-8 8.19 μg/mL [35]
SF-295 >10.0 μg/mL [35]
Launine K (67) HeLa 14.5 μM [37]
MCF-7 62.5 μM [37]
Crassin H (75) HL-60 11.8 ± 2.1 μM [17]
A549 5.2 ± 0.4 μM [17]
Crassifolius A (76) Hep3B 17.91 μM [38]
HepG2 42.04 μM [38]
Cracroson D (339) T24 14.48 ± 0.65 μM [40]
A549 25.64 ± 2.14 μM [40]
Cracroson E (87) T24 22.99 ± 1.76 μM [40]
A549 51.88 ± 14.07μM [40]
Hela 3.9 μM [48]
DU145 7.2 μM [48]
A549 5.8 μM [48]
SGC-7091 13 μM [48]
H1975 10 μM [48]
HL60 12 μM [48]
293T 291.6 μM [48]
LX-2 >500.0 μM [48]
12-O-benzoylphorbol-13-(2-methyl)butyrate (114) K562 15 μM [48]
MOLT-4 12 μM [48]
U937 17 μM [48]
MCF-7 20 μM [48]
Hela 4.6 μM [48]
DU145 4.3 μM [48]
A549 6.9 μM [48]
SGC-7091 10 μM [48]
H1975 3.3 μM [48]
HL60 6.8 μM [48]
293T 420.4 μM [48]
LX-2 >500.0 μM [48]
12-O-tiglyl-7-oxo-5-ene-phorbol-13-(2-methyl)butyrate (115) K562 17 μM [48]
MOLT-4 4.8 μM [48]
U937 21 μM [48]
MCF-7 20 μM [48]
Hela 5.0 μM [48]
DU145 10 μM [48]
A549 19 μM [48]
SGC-7091 23 μM [48]
H1975 10 μM [48]
HL60 10 μM [48]
293T 455.3 μM [48]
LX-2 >500.0 μM [48]
13-O-(2-metyl)butyryl-4-deoxy-4a-phorbol (116) K562 8.0 μM [48]
MOLT-4 9.9 μM [48]
U937 18 μM [48]
MCF-7 24 μM [48]
H1975 10 μM [48]
HL60 10 μM [48]
293T 455.3 μM [48]
LX-2 >500.0 μM [48]
Hela 10 μM [48]
DU145 10 μM [48]
A549 4.5 μM [48]
SGC-7091 5.4 μM [48]
H1975 3.3 μM [48]
HL60 9.8 μM [48]
293T 191.0 μM [48]
LX-2 >500.0 μM [48]
Crotignoid A (117) HL-60 1.61 μM [49]
A549 2.85 μM [49]
Crotignoid B (118) HL-60 22.1 μM [49]
A549 31.0 μM [49]
Crotignoid C (119) HL-60 32.3 μM [49]
A549 5.03 μM [49]
Crotignoid D (120) HL-60 19.8 μM [49]
A549 10.2 μM [49]
Crotignoid F (122) HL-60 44.6 μM [49]
A549 6.96 μM [49]
Crotignoid G (123) HL-60 22.1 μM [49]
A549 3.89 μM [49]
Crotignoid H (124) HL-60 9.97 μM [49]
A549 8.08 μM [49]
Crotignoid I (125) HL-60 14.8 μM [49]
A549 24.4 μM [49]
Crotignoid J (126) HL-60 14.2 μM [49]
A549 29.5 μM [49]
Crotusin A (128) HL-60 12.53 ± 0.37 μM [44]
SMMC-7721 7.06 ± 0.72 μM [44]
A549 9.69 ± 0.41 μM [44]
MCF-7 9.56 ± 0.76 μM [44]
SW480 14.88 ± 0.43 μM [44]
Crotusin B (129) HL-60 19.39 ± 0.46 μM [44]
SMMC-7721 21.13 ± 0.29 μM [44]
A549 14.66 ± 1.66 μM [44]
MCF-7 1.49 ± 0.23 μM [44]
SW480 31.21 ± 3.20 μM [44]
Crotusin C (130) HL-60 4.19 ± 0.15 μM [44]
SMMC-7721 3.87 ± 0.12 μM [44]
A549 2.44 ± 0.35 μM [44]
MCF-7 0.49 ± 0.04 μM [44]
SW480 2.89 ± 0.01 μM [44]
12-O-tiglylphorbol-4-deoxy-4β-phorbol-13-acetate (131) SNU387 59.5 ± 2.1 μM [50]
SNU398 43.7 ± 1.5 μM [50]
12-O-tiglylphorbol-4-deoxy-4β-phorbol-13-hexadecanoate (132) SNU387 30.2 ± 1.4 μM [50]
SNU398 91.2 ± 3.7 μM [50]
13-O-acetylphorbol-4-deoxy-4β-phorbol-20-oleate (133) SNU387 1.9 ± 0.2 μM [50]
SNU398 13.5 ± 1.1 μM [50]
13-O-acetylphorbol-4-deoxy-4β-phorbol-20-linoleate (134) SNU387 0.71 ± 0.08 μM [50]
SNU398 18.2 ± 1.7 μM [50]
4-deoxy-20-oxophorbol 12-tiglyl 13-acetate (135) K562 0.03 μM [51]
A549 6.88 μM [51]
Huh-7 3.85 μM [51]
7-oxo-5-ene-phorbol-13-(2-methylbutyrate) (136) K562 0.03 μM [51]
A549 6.33 μM [51]
Huh-7 20.9 μM [51]
7-hydroxyl-phorbol-5-ene-13-(2-methyl)butyrate (137) K562 0.07 μM [51]
A549 8.86 μM [51]
Huh-7 11.6 μM [51]
13-O-(2-metyl)butyryl-phorbol (139) K562 0.05 μM [51]
A549 43.5 μM [51]
Huh-7 34.2 μM [51]
7-keto-12-O-tiglylphorbol-13-acetate (140) HL-60 6.22 ± 3.24 μg/mL [52]
A549 18.0 ± 9.48 μg/mL [52]
Phorbol-13-isobutyrate (148) HL-60 0.22 ± 0.15 μg/mL [52]
14-epi-hyalic acid (159) HL-60 8.2 μM [63]
Kongeniod A (178) HL-60 1.27 ± 0.24 μM [59]]
A549 5.74 ± 0.25 μM [59]
Kongeniod B (179) HL-60 0.47 ± 0.04 μM [59]
A549 3.25 ± 0.91 μM [59]
Kongeniod C (180) HL-60 0.58 ± 0.17 μM [59]
Crotonkinensin D (188) MCF-7 9.4 ± 1.7 μM [61]
MCF-7/TAMR 2.6 ± 0.9 μM [61]
MCF-7/ADR 18.9 ± 0.6 μM [61]
MDA-MB-231 22.0 ± 0.9 μM [61]
EBC-162 (207) HL-60 15 μg/mL [74]
HT29 15 μg/mL [74]
MCF-7 30 μg/mL [74]
MM96 10 μg/mL [74]
NNF 20 μg/mL [74]
K562 50 μg/mL [74]
EBC-233 (208) HL-60 10 μg/mL [74]
HT29 80 μg/mL [74]
MCF-7 20 μg/mL [74]
MM96 6 μg/mL [74]
NNF 50 μg/mL [74]
K562 50 μg/mL [74]
EBC-300 (209) HL-60 35 μg/mL [74]
HT29 100 μg/mL [74]
MCF-7 100 μg/mL [74]
MM96 80 μg/mL [74]
NNF 80 μg/mL [74]
K562 100 μg/mL [74]
EBC-240 (210) HL-60 45 μg/mL [74]
HT29 80 μg/mL [74]
MCF-7 50 μg/mL [74]
MM96 12 μg/mL [74]
NNF 80 μg/mL [74]
K562 60 μg/mL [74]
EBC-241 (211) HL-60 40 μg/mL [74]
HT29 80 μg/mL [74]
MCF-7 40 μg/mL [74]
MM96 12 μg/mL [74]
NNF 75 μg/mL [74]
K562 60 μg/mL [74]
Furanocembranoid 1 (266) BT474 7.8 μg/mL [83]
CHAGO 7.0 μg/mL [83]
Hep-G2 5.6 μg/mL [83]
KATO-3 5.9 μg/mL [83]
SW-620 6.3 μg/mL [83]
Furanocembranoid 2 (267) BT474 9.5 μg/mL [83]
CHAGO >10 μg/mL [83]
Hep-G2 >10 μg/mL [83]
KATO-3 6.8 μg/mL [83]
SW-620 9.9 μg/mL [83]
Furanocembranoid 3 (268) BT474 9.6 μg/mL [83]
CHAGO 7.1 μg/mL [83]
Hep-G2 5.7 μg/mL [83]
KATO-3 8.2 μg/mL [83]
SW-620 5.6 μg/mL [83]]
Furanocembranoid 4 (269) BT474 9.6 μg/mL [83]
CHAGO 9.3 μg/mL [83]
Hep-G2 6.1 μg/mL [83]
KATO-3 8.1 μg/mL [83]
SW-620 6.0 μg/mL [83]
Laevigatlactone B (272) Hela 38.4 μM [84]
(+)-[1R*,2S*,7S*,8S*,12R*]-7,8-Epoxy-2,12-cyclocembra-3E,10Zdien-20,10-olide (276) PEO1 132 nM [85]
PEO1TaxR 200 nM [85]
(+)-[1R*,4S*,10R*]-4-Hydroxycembra-2E,7E,11Z-trien-20,10-olide (278) PEO1 125 nM [85]
PEO1TaxR 135 nM [85]
Crotontomentosin A (294) Hela 24.0 ± 2.6 μM [88]
Hep G2 87.9 ± 4.5 μM [88]
MDA-MB-231 54.1 ± 2.1 μM [88]
A549 40.6 ± 3.9 μM [88]
Crotontomentosin B (295) Hela >100 μM [88]
Hep G2 28.1 ± 2.1 μM [88]
MDA-MB-231 28.7 ± 3.4 μM [88]
A549 29.1 ± 5.2 μM [88]
Crotontomentosin C (297) Hela 47.9 ± 3.3 μM [88]
Hep G2 83.3 ± 5.3 μM [88]
MDA-MB-231 >100 μM [88]
A549 >100 μM [88]]
Crotontomentosin D (296) Hela 59.7 ± 4.5 μM [88]
Hep G2 >100 μM [88]
MDA-MB-231 49.3 ± 2.8 μM [88]
A549 >100 μM [88]
Crotolaevigatone B (300) A549 21.2 μM [89]
MDA-MB-231 33.4 μM [89]
Crotolaevigatone G (305) A549 25.6 μM [89]
MDA-MB-231 32.7 μM [89]
EBC-324 (311) MCF-7 40 μM [92]
NFF 50 μM [92]
K562 6 μM [92]
EBC-329 (312) MCF-7 13 μM [92]
NFF 40 μM [92]
K562 0.6 μM [92]
ent-3β-hydroxypimara-8(14),9,15-trien-12-one (319) NFF 23 μg/mL [98]
Hela 13 μg/mL [98]
HT 29 13 μg/mL [98]
MCF-7 16 μg/mL [98]
MM96L 2.8 μg/mL [98]
K562 17 μg/mL [98]
EBC-325 (321) MCF-7 20 μM [99]
NFF 6 μM [99]
K562 3 μM [99]
EBC-326 (322) MCF-7 14 μM [99]
NFF 6 μM [99]
K562 6 μM [99]
EBC-327 (323) MCF-7 10 μM [99]
NFF 10 μM [99]
K562 10 μM [99]
3-hydroxycleistantha-13(17),15-diene (325) KATO-3 6.0 μg/mL [93]
SW-620 >10 μg/mL [93]
BT474 6.1 μg/mL [93]
Hep-G2 0.5 μg/mL [93]
CHAGO 5.5 μg/mL [93]
3,4-seco-cleistantha-4(18),13(17),15-trien-3-oic acid (326) KATO-3 9.6 μg/mL [93]
SW-620 >10 μg/mL [93]
BT474 10 μg/mL [93]
Hep-G2 8.6 μg/mL [93]
CHAGO >10 μg/mL [93]
Crotobarin (330) KB 2.5 ± 0.10 μM [101]
HT29 2.1 ± 0.60 μM [101]
A549 0.79 ± 0.15 μM [101]
HL60 0.56 ± 0.02 μM [101]
Crotogoudin (331) KB 1.5 ± 0.03 μM [101]
HT29 1.9 ± 0.25 μM [101]
A549 0.54 ± 0.02 μM [101]
HL60 0.49 ± 0.01 μM [101]
Crotonpyrone A (381) Hela 10.21 μg/mL [120]
NCI-446 6.59 μg/mL [120]
Crotonpyrone B (382) Hela 9.54 μg/mL [120]
[1−9-NαC]-crourorb A1 (385) NCI-ADR/RES 4.8 μM [123]
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3.2. Anti-Inflammatory Activity

Bioassay-guided fractionation of the aerial parts of C. ciliatoglandulifer led to the isolation of tigliane diterpenoids 95, 97, which inhibited the enzymes cyclooxygenases-1 (IC50, 0.001, and 1.0 μM, respectively) and cyclooxygenases-2 (IC50, 2.2 μM, for compound 95) [41]. A tigliane diterpenoid (114) was isolated from the branches and leaves of C. tiglium, which displayed moderate inhibition of the enzymes COX-1 and COX-2, with IC50 values of 0.14 and 8.5 μM, respectively [48]. crotonkinin A (157), isolated from C. tonkinensis, showed anti-inflammatory effect on LPS-induced iNOS-dependent NO production and NOX-dependent ROS production in microglial cells (IC50, 46.2 ± 3.1 μM in NOS; maximum inhibition of NOX activity at 50 μM, 11.2%) [62]. Eight ent-kauranes (169–176) from C. tonkinensis exhibited the anti-inflammatory potential for inhibition of superoxide Anion generation and elastase release. Among them, crotonkinins F (172) displayed significant inhibition of superoxide anion generation (IC50, 2.88 ± 0.52 μM) and elastase release (IC50, 4.44 ± 1.45 μM) [66]. Labdane diterpenoids 251, 254 and 257, 258, isolated from the aerial parts of C. laui, were found to show anti-inflammatory activities in LPS-stimulated RAW 264.7 cells with IC50 values in the range 42.73–93.04 μM [82]. Two grayanane diterpenoids, crotonkinensins A (328) and B (329) from the leaves of C. tonkinensis, were reported to decrease the LPS-induced COX-2 promoter activity in Raw 264.7 cells with IC50 values of 7.14 ± 0.2 and 5.49 ± 0.2 μM, respectively [100]. Two benzoate derivatives (379, 380) were obtained from C. hutchinsonianus. Compound 379 showed significant activity against COX-1 (IC50, 4.95 ± 0.58 μg/mL) and COX-2 (IC50, 2.11 ± 1.3 μg/mL), while compound 380 (IC50, 1.88 ± 0.17 μg/mL) preferentially inhibited COX-2 [119].

3.3. Antifungal Activity

Two benzoate derivatives (379–380) were isolated from C. hutchinsonianus, and exhibited antifungal activity against Candida albicans (IC50, 11.41 ± 1.44, and 5.36 ± 0.01 μg/mL, respectively) [119]. Ursane triterpenoid (348) from the root of C. bonplandianum, displayed the antifungal activity against Calletotricheme camellie (IC50, 10 μg/mL), Fussarium equisitae (IC50, <15 μg/mL), Alterneria alternata (IC50, 10 μg/mL), Curvularia eragrostidies (IC50, <10 μg/mL) and Colletorichum gloeosporiodes (IC50, 15 μg/mL) [107].

3.4. Acetylcholinesterase Inhibitory Activity

An indole alkaloid derivative 376, isolated from the leaves of C. heliotropiifolius, exhibited the acetylcholinesterase inhibitory activity with IC50 values of 17.8 ± 0.6 μM [116]. Compund 378 from C. sylvaticus, also displayed the same activity [118].

3.5. Neurite Outgrowth-Promoting Activity

Two clerodane diterpenoids, crotonpenes A (36) and B (37) were isolated from C. yanhuii, which markedly increased the NGF (20 ng/mL)-induced proportion of neurite bearing cells by 59%, and 47% at 15 μM, respectively [23]. Crotoeurins A–C (40–42) obtained from C. euryphyllus, were found to display neurite outgrowth-promoting activity on NGF mediated PC12 cells at concentration of 10 μM. The percentages of neurite-bearing cells were 9.72%, 14.90%, and 7.14%, respectively [25].

3.6. Other Activities

Besides the above activities, other biological activities have also been reported. Crotonolide G (32), from the aerial parts of C. laui, was found to exhibit potent antibacterial activity (MIC, 43.4 μM) against four strains of Gram-positive bacteria, namely, Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, and Bacillus subtilis [21]. Crassifolin H (39) was obtained from roots of C. crassifolius as an angiogenic inhibitor by reducing vessel formation to 59.3% at 15 μg/mL [34]. Tigliane diterpene (111) was isolated from the leaves of C. mauritianus, which inhibited chikungunya virus-induced cell death in cell culture with EC50s of 4.0 ± 0.8 μM [43]. The leaves of C. tiglium yielded two tigliane diterpenoids (135, 136), which displayed significant antitubercular activities with MIC values of 19.5, and 20.9 μM, respectively [51]. Compounds (162–165) were four ent-kaurane diterpenes from C. tonkinensis, which significantly stimulated differentiation in osteoblasts [64]. From the twigs and leaves of C. cascarilloides, two crotofolane diterpenoid alkaloids cascarinoids B–C (226, 227) were obtained, both of which displayed moderate activities against the ConA-induced proliferation of T lymphocyte cells and/or LPS-induced proliferation of B lymphocyte cells with IC50 values ranging from 6.14 to 16.27 μM [71]. Meroditerpenoid (336), from C. steenkampianus, showed antiplasmodial activities of 15.8 (D10), 9.1 (W2), and 9.4 (Dd2) μM [102]. Indole alkaloid (377) was found in C. mauritianus with antioxidant activity (IC50, 30.0.0 ± 0.7 μM) by the DPPH radical scavenging assay [117]. Bioactivity-guided fractionation of the root bark of C. jatrophoides resulted in the isolation of musidunin (388) and musiduol (389), both of which showed insect antifeedant activities (PC50, 3 μg/mL, PC95, 10 μg/mL; PC50, 4 μg/mL, PC95, 20 μg/mL, respectively) against the second-instar larvae of Pectinophora gossypiella in a leaf disk assay [126].

4. Conclusions

In the present review, we systematically summarized the chemical constituents and biological activity studies of Croton species covering from 2006 to 2018. To date, a total of 399 new compounds were reported from Croton species, which included 339 diterpenoids, seven sesquiterpenoids, 21 glycosides, eight alkaloids, and 24 miscellaneous compounds (Figure 14). Obviously, diterpenoids are characteristic components for Croton species. The diterpenoids with clerodane, tigliane, kaurane, crotofolane, labdane, and cembrane skeletons are among the most studied diterpenoids isolated from Croton species (Figure 14). Although the current studies have shown that these isolated compounds from Croton species possessed diversified biological activities, many compounds have never been biologically tested. Moreover, most studies conducted so far have focused mainly on in vitro cytotoxic assays. Further studies on the mechanism of actions and the structure activity relationship are needed in order to provide a better understanding of the chemical constituents from Croton species as potential medicines. Increasing interest in the chemistry and pharmaceutics of Croton species may promote new progress in finding and developing novel compounds.

Figure 14.

Figure 14

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The percentage of each type of compounds (left), the percentage of each type of diterpenoids (right) from Croton Species.

Author Contributions

W.-H.X. classified the chemical constituents and drafted the structural formulas, wrote the manuscript; W-Y L. collected literatures; Q.L. managed references, overall responsibility.

Funding

We are thankful for financial supports from the Natural Science Foundation of China (NSFC) (21362035); The Initial Foundation of Scientific Research for the introduction of talents from Southwest Forestry University for Wen-Hui Xu (20130916); and Opening Research Foundation from Key Laboratory for Forest Resources Conservation and Utilization in the Southwest Mountains of China, Ministry of Education, Southwest Forestry University (KLE201807).

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Sample Availability: Samples of the compounds are not available from the authors.

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