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. 2021 Jun 23;12(8):1374–1380. doi: 10.1039/d0md00372g

Design, synthesis and biological evaluation of combretastatin A-4 sulfamate derivatives as potential anti-cancer agents†

Leilei Huang 1, Jinwen Huang 1,2,3,✉, Hui Nie 1, Yingzi Li 1, Lixing Song 1, Fanhong Wu 1,2,✉
PMCID: PMC8372205  PMID: 34458740

Abstract

A series of combretastatin A-4 (CA-4) sulfamate derivatives were synthesized and their structure–activity relationship on tubulin, arylsulfatase and tumor cell antiproliferation inhibition was studied. Among them, compound 16a showed excellent potency as well as CA-4 under the same conditions against six tumor cells including HTC-116, HeLa, HepG2, MGC803, MKN45 and MCF-7 cells, respectively. Molecular docking revealed that several important hydrogen bond interactions were formed between the sulfamate group of 16a and the colchicine binding site of tubulin and steroid sulfatase respectively. Although compound 16a was less active than CA-4 in regard to its in vitro activity as an inhibitor of tubulin polymerization, it was effective as an inhibitor of arylsulfatase. This novel combretastatin A-4 sulfamate derivative has the potential to be developed as a dual inhibitor of tubulin polymerization and arylsulfatase for cancer therapy.

A series of combretastatin A-4 (CA-4) sulfamate derivatives were synthesized and their structure–activity relationship on tubulin, arylsulfatase and tumor cell antiproliferation inhibition was studied.graphic file with name d0md00372g-ga.jpg

The occurrence and development of cancer is a complex and long process, and cancer is one of the major causes for the increase in world mortality.1–3 In particular, breast cancer is the most common cancer with high incidence rates in women, making up about one third of global cancer diagnoses for women, and it is one of the major health problems in the world.4–7 In the past few decades, great progress was made in molecular-targeted anti-tumor drug research.8 Tubulin and arylsulfatase are promising targets in cancer therapy. Tubulin is the fundamental unit of microtubules in the cell, and it plays a critical role in maintaining the shape, movement and intracellular material transportation in the cell. Tubulin targeted inhibitors are effective in the treatment of cancer.9 There are three major binding pockets in tubulin, which were named after three different drugs, paclitaxel, vincristine and colchicine, respectively. Tubulin inhibitors binding to these pockets can arrest tumor cell mitosis and induce apoptosis.9,10 Paclitaxel and vincristine are effective chemotherapy drugs widely used in the clinic, and some marketed drugs were developed targeting the paclitaxel and vincristine binding sites.10 However, colchicine was not used in treating cancer due to its high toxicity, and studies on inhibitors targeting colchicine binding sites are one of the hotspots in antineoplastic drug research.11

Arylsulfatases are one kind of a protein family in charge of the hydrolysis of sulfonates, and they play a significant role in the hormonal regulation in cells, the degradation of cell components and signaling pathway regulation.12 The abnormal activity of arylsulfatases in the body is closely related to the growth of tumors. Currently, there are four extensively studied arylsulfatases, namely lysosomal arylsulfatases (ARS-A and ARS-B), endoplasmic reticulum arylsulfatase (ARS-C) and extracellular arylsulfatase (Hsulf-1). In the clinic, the activity of ARS-A and ARS-B has become an important indicator in tumor diagnosis as the ARS activity in urine would significantly increase in all types of tumor patients.13 ARS-C, also known as steroid sulfatase (STS), is majorly responsible for adjusting the balance of hormone levels (Scheme 1) by hydrolysis of estrone sulfate (E1S) and dehydroepiandrosterone sulfate (DHE-AS) in order to release estrone and dehydroepiandrosterone (DHEA). The abnormal state of STS will imbalance the hormone levels in the body as well as promote the growth and proliferation of cancer cells. Steroid sulfatase (STS) inhibitors are an effective therapy for the treatment of hormone dependent cancer such as breast and cervical cancer by inhibiting the hydrolysis of E1S.14 In the past few years, a lot of steroid sulfatase inhibitors (1–5, Fig. 1), including stilbene compounds, have been developed and they exhibit good inhibitory activity against breast cancer cells via inhibiting steroid sulfatase.15 The sulfamate group is an essential pharmacophore for potency, and estrone-3-O-sulfamate (EMATE, 1), the sulfamate derivative of estrone, is a typical representative of this kind of inhibitor.16

Scheme 1. The role of steroid sulfatase in hormone regulation.

Scheme 1

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Fig. 1. Chemical structures of 1–12.

Fig. 1

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Combretastatin A-4 (CA-4, 6a) and combretastatin A-1 (CA-1, 7) are cis-stilbene type natural products originally isolated from the South African bushwillow tree Combretum caffrum. They inhibit tubulin polymerization by interacting with the colchicine-binding sites of tubulin, thus arresting the mitosis of tumor cells and inducing their apoptosis. In addition, CA-4 disrupts tumor vasculaures at a nontoxic dose resulting in tumor cells starving to death without affecting the healthy cell's blood supply.17 Efforts directed toward the discovery of more potent and selective vascular disrupting agents continue on a global basis.18 In recent years, a large number of structure modifications were made to find more potent CA-4 analogues,19,20 and among them, AVE-8062A (10) and CA-4P (11) have entered phase II/III clinical trials (Fig. 1).20 Structure–activity relationship studies indicate that the cis-conformation is crucial for potency. Our groups also have made a lot of progress in finding more potent CA-4 analogues with improved properties by using the twin drug, prodrug and fluorine modification strategies.21

In addition to the strong arylsulfatase inhibition, the anti-tumor mechanism of EMATE is also related to its weak tubulin inhibition activity (IC50 = 25.90 μM, Table 2). 2-Methoxyestradiol (2-ME), an endogenous metabolite of 17-estradiol, is also a weak tubulin inhibitor (IC50 ≈ 40 μM) and it can inhibit microtubule assembly and induce G2/M arrest and apoptosis in many actively dividing cell types while sparing quiescent cells.22 2-ME can also bind to the colchicine site of tubulin. Therefore, it has potent antineoplastic activity as an apoptosis inducer and an angiogenesis inhibitor. However, 2-ME is ineffective for arylsulfatase inhibition as compared to EMATE.22 The sulfamide group is a widely used pharmacophore in medicinal chemistry as it possess both hydrogen bond donors and acceptors. There are many reports about sulfamate modification of other molecular structures as a potent dual inhibitor of carbonic anhydrase and steroid sulfatase.23 Inspired by the structure and the difference of activity in tubulin and sulfatase inhibition between EMATE and 2-ME, we speculated that sulfamate modification of CA-4 would lead to the foundation of effective dual inhibitors of both tubulin and steroid sulfatase. We hope to obtain a drug candidate with better potency, stability and pharmacokinetic profiles than CA-4 through the sulfamate derivatives of CA-4 and further structure–activity relationship (SAR) studies (Fig. 2). Herein, we reported the synthesis and biological evaluation of novel combretastatin analogues, while also discussing the molecular docking study and the SAR analysis.

The in vitro inhibitory activities of combretastatin A-4 sulfamate derivatives against arylsulfatase and tubulin.

Entry R1 R2(R3)N X IC50 ± SD (μM)
Arylsulfataseb Tubulinc
16a (Z) OMe NH2 O 6.16 ± 0.55 6.60 ± 0.80
16b (E) OMe NH2 O 12.86 ± 0.25 55.70 ± 6.00
16c (Z) OCF2H NH2 O 4.64 ± 1.42 72.60 ± 10.7
16e (Z) OEt NH2 O 90.19 ± 7.83 3.10 ± 1.10
16g (Z) H NH2 O 0.47 ± 0.01 >100
16i (Z) OMe NHMe O >100 1.80 ± 0.00
16j (Z) OMe N(Me)2 O >100 12.50 ± 1.50
17a a OMe NH2 O >100 >100
19a (Z) OMe NH2 NH >100 86.20 ± 6.40
EMATE — — — 5.01 ± 0.01 25.90 ± 7.10
CA-4 — — — >100 1.00 ± 0.20
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a

Saturated bond linked compound.

b

Steroid sulfatase.

c

Tubulin polymerization.

Fig. 2. The design of sulfamate derivatives of CA-4.

Fig. 2

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Firstly, compound 16a, the sulfamate modified CA-4 (6a), was synthesized and its antiproliferation activity was compared with that of CA-4 as the positive control. To our delight, compound 16a showed excellent anti-tumor activity with respect to CA-4 under the same conditions. Next, we designed a number of combretastatin A-4 sulfamate and sulfamide derivatives to explore their structure–activity relationship. The synthetic procedures are outlined in Schemes 2 and 3. The aldehyde intermediate (13) was purchased or prepared following a reported protocol.21b The hydroxyl group of 13 was protected with trityl to give 14. A (Z/E)-stilbene mixture was obtained from the aldehyde intermediates (14 or 13e, in Schemes 2 and 3) and triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide (15) via the Wittig reaction, followed by deprotection of the trityl group or reduction of the nitro group to give 3-hydroxyl or 3-amino substituted (on the B ring) stilbenes (6 and 9, Schemes 2 and 3). Their Z and E isomers were separated by flash column chromatography. Compounds 6 and 9 were further reacted with sulfamoyl chloride respectively to achieve the corresponding sulfamate (16) and sulfamide (19) derivatives of stilbene. The diphenylethane sulfamate and sulfamide derivatives (17 and 20) were obtained from the Pd/C catalyzed hydrogenation of 16 and 19.

Scheme 2. Synthetic route of combretastatin A-4 sulfamate derivatives. Reagents and conditions: a) Ph3CCl(TrCl), THF, Et3N, rt, 2 h; b) n-BuLi, THF, −78 °C, 30 min, then adding 14/THF solution, −78 °C–RT, overnight; c) 37% HCl (aq.), toluene, rt, 2 h; d) NaH, DMF, RSO2Cl (R = NH2, NHMe, N(Me)2), 0 °C to RT, overnight; e) H2 (1 atm), 10% Pd/C, EtOH, rt, 3 h.

Scheme 2

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Scheme 3. Synthetic route of combretastatin sulfamide derivatives. Reagents and conditions: a) n-BuLi, THF, −78 °C, 30 min, then adding 13e/THF solution, −78 °C–rt, overnight; b) Zn, CH3COOH, 2 h, rt; c) NaH, DMF, NH2SO2Cl, 0 °C–rt, overnight; d) H2 (1 atm), 10% Pd/C, EtOH, rt, 3 h.

Scheme 3

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The in vitro antiproliferative activity of these compounds were evaluated via the CCK-8 assay by using CA-4 and EMATE as the positive control. Six human tumor cell lines, including the HTC-116, HeLa, HepG2, MGC803, MKN45 and MCF-7, were tested. The results are summarized in Table 1. Among all the analogues, only compound 16i, the monomethylated 16a, showed comparable potency (IC50 = 3.4–11.3 nM) to 16a (IC50 = 3.6–9.5 nM) and CA-4 (IC50 = 2.9–8.1 nM) on the six tumor cell lines, except that its inhibitory activity (IC50 = 0.53 μM) on MCF-7 cells is slightly less potent than that of 16a (IC50 = 0.11 μM) and CA-4 (IC50 = 0.14 μM). As for compound 16j, the dimethyl substituted 16a, its potency was reduced although it showed stronger potency on HTC-116 cells (IC50 = 0.37 μM) than on the other five tumor cell lines (IC50 = 7.14–14.26 μM). The replacement of sulfamate with sulfamide (19a) also led to a potency decrease compared with 16a. 19a showed better potency (IC50 = 0.27, 0.75, 0.50 μM) on HeLa, HepG2, and MGC803 than on the other three cell lines (HCT-116, MKN45 and MCF-7, IC50 = 3.29, 9.56, 11.19 μM). The electronic and steric effects of R-substitution also has a great influence on potency. When the methoxyl group of 16a was replaced with a hydrogen (16g, R = H), difluoromethoxy (16c, R = OCF2H) or ethoxy (16e, R = OEt) group, their cellular potency decreased compared with that of 16a and CA-4. In addition, it was observed that the cis-double bond linked compounds (16a, 16c, 16e, 16g and 19a) showed better cellular potency than the trans-double bond (16b, 16d, 16f, 16h and 19e) and saturated bond linked compounds (17a–17d, 20). A CA-4 sulfate derivative (CA4S, Fig. 2) was identified as a phase II metabolite of CA4.24 We have also synthesized it as a control; however, it is ineffective in tumor cell cytotoxicity assays (IC50 > 100 μM).

The in vitro antiproliferation activities of combretastatin A-4 sulfamate and sulfamide derivatives against on six human tumor cellsa.

graphic file with name d0md00372g-u1.jpg
Compounds IC50 (mean ± SD, μM)a
Entry R R1(R2)N X HTC-116 HeLa HepG2 MGC803 MKN45 MCF-7
CA-4 — — — 0.0047 ± 0.0008 0.0029 ± 0.0001 0.0029 ± 0.0007 0.0060 ± 0.0006 0.0081 ± 0.0004 0.14 ± 0.02
EMATE — — — 0.90 ± 0.04 0.63 ± 0.06 0.85 ± 0.05 0.48 ± 0.09 0.54 ± 0.12 0.07 ± 0.10
16a (Z) OMe NH2 O 0.0050 ± 0.0005 0.0061 ± 0.0003 0.0036 ± 0.0002 0.0047 ± 0.0006 0.0095 ± 0.0004 0.11 ± 0.04
16b (E) OMe NH2 O 1.57 ± 0.07 4.50 ± 0.07 0.87 ± 0.09 2.98 ± 0.07 10.52 ± 0.04 5.44 ± 0.05
16c (Z) OCF2H NH2 O 9.11 ± 0.04 7.82 ± 0.05 4.81 ± 0.06 9.00 ± 0.05 12.52 ± 0.04 0.29 ± 0.05
16d (E) OCF2H NH2 O 12.84 ± 0.03 8.42 ± 0.04 5.54 ± 0.05 9.24 ± 0.04 13.84 ± 0.04 13.79 ± 0.03
16e (Z) OEt NH2 O 0.55 ± 0.07 0.48 ± 0.08 0.41 ± 0.05 0.27 ± 0.07 0.32 ± 0.07 0.30 ± 0.06
16f (E) OEt NH2 O 9.12 ± 0.04 5.64 ± 0.05 2.63 ± 0.07 7.63 ± 0.05 8.05 ± 0.05 13.71 ± 0.03
16g (Z) H NH2 O 9.50 ± 0.03 16.30 ± 0.03 9.36 ± 0.05 8.53 ± 0.04 15.32 ± 0.02 11.10 ± 0.04
16h (E) H NH2 O 40.30 ± 0.04 19.00 ± 0.03 11.85 ± 0.03 27.03 ± 0.02 25.04 ± 0.02 27.44 ± 0.02
16i (Z) OMe NHMe O 0.0113 ± 0.0003 0.0034 ± 0.0005 0.0039 ± 0.0010 0.0037 ± 0.0006 0.0073 ± 0.0003 0.53 ± 0.03
16j (Z) OMe N(Me)2 O 0.37 ± 0.07 14.26 ± 0.04 9.96 ± 0.03 7.14 ± 0.03 8.95 ± 0.37 11.06 ± 0.04
19a (Z) OMe NH2 NH 3.29 ± 0.77 0.27 ± 0.06 0.75 ± 0.06 0.50 ± 0.07 9.56 ± 0.09 11.19 ± 0.06
19b (E) OMe NH2 NH 8.65 ± 0.04 0.38 ± 0.05 7.53 ± 0.06 6.19 ± 0.06 18.87 ± 0.03 17.09 ± 0.04
17a b OMe NH2 O 2.63 ± 0.08 9.04 ± 0.04 1.06 ± 0.05 3.61 ± 0.08 11.87 ± 0.04 5.91 ± 0.06
17a b OCF2H NH2 O 26.48 ± 0.02 35.65 ± 0.01 15.88 ± 0.02 23.26 ± 0.02 71.38 ± 0.02 52.74 ± 0.03
17c b OEt NH2 O 10.16 ± 0.03 2.930 ± 0.07 3.65 ± 0.07 3.59 ± 0.06 7.67 ± 0.06 14.75 ± 0.02
17d b H NH2 O 52.49 ± 0.02 27.06 ± 0.03 12.03 ± 0.03 17.64 ± 0.04 25.70 ± 0.03 >100
20 b OMe NH2 NH 30.63 ± 0.04 2.926 ± 0.07 8.10 ± 0.05 8.21 ± 0.04 73.88 ± 0.05 20.13 ± 0.03
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a

The experiment was carried out using an EnoGeneCellTM counting Kit-8 (CCK-8) assay.

b

Saturated bond linked compound.

In order to verify the effectivity of these novel sulfamate derivatives of CA-4 on both arylsulfatase and tubulin, we tested their inhibitory activity on steroid sulfatase and tubulin polymerization with EMATE and CA-4 as the control, and the results are summarized in Table 2. The half inhibition rate (IC50) of EMATE on steroid sulfatase and tubulin polymerization is 5.01 μM and 25.90 μM, respectively. The test inhibitory potency of combretastatin A-4 on tubulin (IC50 = 1.0 μM) is consistent with literature reports; however, it is ineffective on steroid sulfatase. When the hydroxyl of CA-4 was modified by sulfamide (16a), it showed a slightly lower potency (IC50 = 6.60 μM) on tubulin polymerization inhibition than CA-4 together with a comparable potency (IC50 = 6.16 uM) on steroid sulfatase to that of EMATE. By comparing the anti-proliferation activities and the relationship of the steroid sulfatase and tubulin inhibition potencies of CA-4 and 16a, we can conclude that 16a is a dual inhibitor, with the additional steroid sulfatase inhibition compensating for the lost contribution of tubulin polymerization inhibition to its anti-tumor activity. From the SAR analysis (described in the ESI†) based on arylsulfatase and tubulin polymerization inhibition (Table 2), we can conclude the following: 1) the cis-isomers show better activity for arylsulfatase and tubulin polymerization inhibition than the trans-isomers and saturated bond linked analogues. 2) The electronic and steric effects of R-groups are different on the two targets. Electron withdrawing groups are favorable for arylsulfatase inhibition but are unfavorable for tubulin inhibition at the same time. Meanwhile, bulky groups are favorable for tubulin inhibition but unfavorable for arylsulfatase inhibition. 3) The amino group of 16a probably has a critical hydrogen bond interaction with the binding site of both targets. By comparing with 16a, monomethyl substitution increased the potency while dimethyl substitution decreased the potency for tubulin polymerization inhibition. However, the substitution of the amino group of 16a will lead to the loss of potency on arylsulfatase. 4) Replacing the sulfamate group with sulfamide decreases the potency on both targets. 5) Tubulin inhibition plays a dominant role over arylsulfatase inhibition in the anti-tumor activity in this kind of dual inhibition.

Compound (16a) was further selected for molecular docking studies in order to explore how the CA-4 sulfamate derivatives interact with tubulin and steroid sulfatase. The protein complexes tubulin (PDB: 5LYJ)24 and human placental estrone/DHEA sulfatase (PDB: 1P49)25 were used for simulation in Sybyl-X 2.0. The force field was Tripos with an 8 Å cutoff for non-bonded interactions, and the atomic point charges were also calculated with the Gasteiger–Huckel method. Minimization was achieved using the steepest descent method for the first 100 steps, followed by the Broyden–Fletcher–Goldfarb–Shanno (BFGS) method until the root-mean-square (RMS) of the gradient became <0.005 kcal/(mol Å). The Surflex-Dock module implemented in the Sybyl program was used for the docking study. The colchicine-binding site of tubulin was used and verified from the original ligand (CA-4) for docking (total score = 8.34, similarity = 0.73). The docking score and similarity of 16a is 6.27 and 0.45, respectively. As shown in Fig. 3, the A/B ring binding mode of 16a is almost identical to that of CA-4, both having van der Waals interaction with the same hydrophobic pocket formed by the amino acid residues VAL238, CYS241, LEU248, ALA250, LEU255, ALA316 and LYS352. The hydroxyl group of CA-4 formed a hydrogen bond with THR179, while the sulfamide group of 16a formed two hydrogen bonds with ALA180 and ASN349.

Fig. 3. The binding information of CA-4 in the co-crystal structure (A, PDB code: 5LYJ) and the docking result of 16a (B).

Fig. 3

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Both EMATE and 16a were docked into the same binding pocket of steroid sulfatase, and their docking scores were 6.16 and 5.34, respectively. As shown in Fig. 4, the hydrophobic part of EMATE and 16a were superimposable, having van der Waals interaction with the hydrophobic pocket formed by the residues VAL101, LEU103, VAL486, HIS485, PHE488, etc. The sulfamate group of 16a formed four important hydrogen bonds with the residues THR165, LYS134, ASP36 and LYS368 in the binding pocket. As for EMATE, there are six hydrogen bonds between the sulfamate group and the residues THR76, THR165, LYS134, ASP342 and ASP36. These important hydrogen bonding interactions explain why 16a is less potent than EMATE, and the methylation of the sulfamate group (16i and 16j) leads to the loss of potency for steroid sulfatase inhibition.

Fig. 4. The docking result of EMATE (A) and 16a (B) with steroid sulfatase (PDB code: 1P49).

Fig. 4

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In summary, we have synthesized a few novel combretastatin sulfamate derivatives, and evaluated their activities on steroid sulfatase, tubulin and tumor cell proliferation inhibition. Among them, compound 16a has a well-balanced sulfatase, tubulin and cellular inhibition potency. The SAR analysis and molecular docking study indicate that the sulfamate group is crucial for sulfatase inhibition and helpful to form additional hydrogen bonds with the colchicine-binding site of tubulin. These results highlighted that compound 16a is a promising anticancer agent, and may be valuable in finding more effective treatments for cancer. To the best of our knowledge, this is the first sulfamate analogue of CA-4. Further biological investigation is being conducted and the progress will be reported in the future.

Funding sources

National Natural Science Foundation of China; Innovation Program of Shanghai Municipal Education Commission; Shanghai Institute of Technology.

Abbreviations

STS

Steroid sulfatase

E1S

Estrone sulfate

DHE-AS

Dehydroepiandrosterone sulfate

DHEA

Dehydroepiandro-sterone

CA-4

Combretastatin A-4

EMATE

Estrone-3-O-sulfamate

SAR

Structure–activity relationship

Author contributions

All the authors have given approval to the final version of this manuscript.

Conflicts of interest

The authors declare no competing financial interests.

Supplementary Material

MD-012-D0MD00372G-s001

Acknowledgments

Financial support from the National Natural Science Foundation of China (No. 21472126, 21302128, 21672151), the Innovation Program of Shanghai Municipal Education Commission (No. ZZZZyyx16006) and Shanghai Institute of Technology (No. YJ2016-41) is gratefully acknowledged. We are also thankful to Nanjing OGPharmaceutical Co. Ltd., Shanghai Research Institute of Chemical Industry Co. Ltd. and Shandong Huawei Pharmaceutical Co. Ltd. for their help in bioassays.

†

Electronic supplementary information (ESI) available. See DOI: 10.1039/d0md00372g

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