Synthesis and Anticancer Activity of New Thiopyrano[2,3-d]thiazoles Based on Cinnamic Acid Amides

Andrii Lozynskyi; Borys Zimenkovsky; Roman Lesyk

doi:10.3797/scipharm.1408-05

. 2014 Sep 15;82(4):723–733. doi: 10.3797/scipharm.1408-05

Synthesis and Anticancer Activity of New Thiopyrano[2,3-d]thiazoles Based on Cinnamic Acid Amides

Andrii Lozynskyi ¹, Borys Zimenkovsky ¹, Roman Lesyk ^1,^*

PMCID: PMC4475803 PMID: 26171321

Abstract

Novel rel-(5R,6S,7S)-2-oxo-5-phenyl-7-aryl(hetaryl)-3,7-dihydro-2H-thiopyrano [2,3-d]thiazole-6-carboxylic acid amides were synthesized in a hetero-Diels-Alder reaction with a series of cinnamic acid amides. The synthesized compounds were tested for their anticancer activity in vitro in the standard National Cancer Institute 60 cancer cell line assay. Promising compounds 3e, 3g, and 3h with moderate antitumor activity were identified among the synthesized series.

Keywords: hetero-Diels-Alder reaction; Cynnamic acid amides; 5-Ylideneisorhodanines; Thiopyrano[2,3-d][1,3]thiazoles; Anticancer activity

Introduction

Investigations of thiopyrano[2,3-d]thiazole derivatives, the isosteric mimics of biologically active 5-ylidene-4-thiazolidinones, led to the synthesis of compounds with anticancer, antitrypanosomal, and antimycobacterial properties which can provide an opportunity to further study and explore the pharmacological activity of these heterocyclic systems in the future [1–13]. We decided to combine in a single heterocyclic system the thiazolidinone moiety and a fragment of cinnamic acid (Sch. 1). Cinnamic acid and its derivatives exhibit antitumor, antimicrobial, antifungal action and act as histamine H₃-receptor antagonists [14–16]. Consequently, we have synthesized thiopyrano[2,3-d]thiazoles using cinnamic acid amides as the dienophile in the reaction of hetero-Diels-Alder.

Sch. 1. — Background for the synthesis of target compounds

In addition, heterodiene synthesis allows the fixing of the biologically important 4-thiazolidinone fragment in a rigid fused system, preserving its biological activity. Moreover, the combination of thiazole and thiopyran in a fused heterosystem is a precondition for creating ligand-target binding and enhances the potential selectivity to biotargets. This approach suggests the critical impact of the substituent on the biological activity with particular selectivity to various cancer cell lines.

Results and Discussion

Chemistry

The starting 5-aryl(hetaryl)idene-4-thioxo-2-thiazolidinones 1a–d were obtained by the treatment of 4-thioxo-2-thiazolidinone with the appropriate aldehydes in glacial acetic acid with a catalytic amount of fused sodium acetate [4, 12]. The cinnamic acid amides were synthesized by the interaction of the corresponding cinnamic acid chloride with 4-substituted anilines, morpholine, and 2-aminopyridine in anhydrous dioxane. The hetero-Diels-Alder reaction of 2a–f with 5-aryl(hetaryl)idene-4-thioxo-2-thiazolidinones 1a–d yielded a series of novel rel-(5R,6S,7S)-2-oxo-5-phenyl-7-aryl(hetaryl)-3,7-dihydro-2H-thiopyrano[2,3-d]thiazole-6-carboxylic acid amides (Sch. 2).

Sch. 2. — Synthesis of 2-oxo-5-phenyl-7-aryl(hetaryl)-3,7-dihydro-2H-thiopyrano[2,3-d]-thiazole-6-carboxylic acid amides

The structure of the synthesized compounds was confirmed by ¹H- and ¹³C NMR. We found the features of the stereochemistry of the above hetero-Diels-Alder reaction. Particularly, we have observed that cinnamic acid amides in the [4+2]-cyclocondensation of 5-arylideneisorhodanines form a pair of rel-(5R,6S,7S)-diastereomers. This claim is based on the coupling constant values within 10.4–11.5 Hz and the spectral signals of the thiopyran fragment (triplet and two doublets at 3.40–4.87 ppm), which prove an axial-axial interaction of 5-H, 6-H and 6-H, 7-H proton pairs. Importantly, a similar pattern was observed earlier for cinnamic acids as the dienophile in the reactions of hetero-Diels-Alder [11, 12].

Biological Activity

The synthesized rel-(5R,6S,7S)-2-oxo-5-phenyl-7-aryl(hetaryl)-3,7-dihydro-2H-thiopyrano-[2,3-d]thiazole-6-carboxylic acid amides were selected by the National Cancer Institute (NCI) Developmental Therapeutic Program (www.dtp.nci.nih.gov) for the in vitro cell line screening to investigate their anticancer activity. Anticancer assays were performed according to the NCI protocol, which is described elsewhere [5–7, 17]. The compounds were evaluated for antitumor activity against 60 cancer lines at a 10 µM concentration. The human tumor cell lines were derived from nine different cancer types: leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers. The screening results are shown in Table 1.

Tab. 1.

Cytotoxic activity of the tested compounds in the concentration 10^-5 M against 60 cancer cell lines

Test cpds.	Average growth, %	Range of growth, %	Most sensitive cell line growth, % (cancer line/type)
3b	82.76	53.05–106.26	53.05 (RPMI-8226 / leukemia)
			61.05 (SF-295 / CNS cancer)
3c	101.41	88.61–117.37	88.61 (RXF 393 / renal cancer)
3e	57.09	26.38–94.10	27.11 (MOLT–4 / leukemia)
			26.38 (HCT–116 / colon cancer)
			32.89 (SF–295 / CNS cancer)
			35.53 (PC–3 / prostate cancer)
			33.44 (MCF7 / breast cancer)
			*33.81 (T–47D* / breast cancer)**
3g	57.89	26.51–91.71	*26.51 (MOLT–4* / leukemia);**
			*37.02 (RPMI–8226* / leukemia)**
			*39.39 (A549/ATCC* / non-small cell lung cancer)**
			*32.09 (HCT–116* / colon cancer)**
			*33.18 (SF–295* / CNS cancer)**
			*33.99 (PC–3* / prostate cancer)**
			*31.77 (MCF7* / breast cancer)**
			*39.88 (T–47D* / breast camcer)**
3h	77.68	–42.92–114.10	*30.79 (HOP–92* / non-small cell lung cancer)**
			*-42.92 (NCI–H522* / non-small cell lung cancer)**
			*35.63 (SK-MEL-5* / melanoma)**
			*-21.73 (CAKI-1* / renal cancer)**
			*37.39 (UO-31* / renal cancer)**
3i	80.64	51.43–119.84	57.75 (SF-295 / CNS cancer)
			51.43 (PC-3 / prostate cancer)
			59.03 (MCF7 / breast cancer)
3j	88.76	61.65–112.27	61.65 (SNB-75 / CNS cancer)
3k	95.84	72.63–120.48	72.63 (T-47D / breast cancer)
3l	100.81	73.58–120.80	77.27 (SNB-75 / CNS cancer)
			78.29 (UO-31 / renal cancer)
			73.58 (T-47D / breast cancer)
3m	96.07	73.69–110.93	73.69 (SR / leukemia);

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The tested compounds showed different levels of activity on various cancer cell lines. The most active compounds were 3e, 3g, 3h, being highly potent in certain lines of cancer, but they had almost no activity in others. Compounds 3e, 3g have a selective effect on the growth of MOLT-4 (leukemia), HCT-116 (colon cancer), SF-295 (CNS cancer), PC-3 (prostate cancer), MCF7, and T-47D (breast cancer) cancer cell lines in comparison with others.

The empirical SAR study (Sch. 3) revealed that:

(1) the anticancer activity of the synthesized compounds is sensitive to the nature of the amide fragment in position 6 and substitution in position 7 of the thiopyrano[2,3-d]thiazole moiety;

(2) introduction of p-Me- or p-Cl-C6H4 groups in the amide fragment enhances the potency;

(3) the loss of anticancer activity is caused by the introduction of morpholin and pyridine fragments in position 6 or substitution of the arylamide moiety by OH or sulfanilamido groups;

(4) synthesized thiopyrano[2,3-d]thiazole-6-carboxylic acid amides with p-Me- and p-Cl-C6H4 groups in postion 7 have the most preferable level of activity compared to other derivatives.

Experimental

Chemistry

All materials were purchased from Merck, Sigma-Aldrich, or Lancaster and were used without purification. 5-Aryl(hetaryl)idene-4-thioxo-2-thiazolidinones 1a-d were employed as starting materials and prepared according to the method described previously [4, 12]. Melting points were determined in open capillary tubes and were uncorrected. The elemental analyses (C, H, N) were performed using the Perkin—Elmer 2400 CHN analyzer and were within 0.4% of the theoretical values. The ¹H- and ¹³C NMR spectra were recorded on the Varian Gemini 400 MHz or Bruker 125 MHz for frequencies of 100 MHz in DMSO-d₆ using tetramethylsilane as an internal standard. Chemical shifts are reported in ppm units with the use of a δ scale. The purity of all obtained compounds was checked by ¹H-NMR and TLC.

General Procedure of the Hetero-Diels-Alder Reaction Affording 3a-m

A mixture of appropriate 5-aryl(hetaryl)idene-4-thioxo-2-thiazolidinone (5 mmol) and cinnamic acid amide (5.5 mmol) was refluxed for 4–7 h with a catalytic amount of hydroquinone (2–3 mg) in 15 ml of glacial acetic acid and left overnight at room temperature. The obtained solid products were collected by filtration, washed with water, methanol (5–10 ml), diethyl ether, and recrystallized from the appropriate solvent.

rel-(5R,6S,7S)-N-(4-Chlorophenyl)-7-(4-hydroxyphenyl)-2-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carboxamide (3a)

Yield: 59%, mp 234–236°C (EtOH). ¹H NMR (400 MHz, DMSO-d₆) δ: 3.47 (t, 1H, J = 10.4 Hz, 6-H), 4.21 (d, 1H, J = 10.4 Hz, 7-H), 4.83 (d, 1H, J = 10.4 Hz, 5-H), 6.70 (d, 2H, J = 8.8 Hz, arom.), 7.00 (d, 2H, J = 8.8 Hz, arom.), 7.12 (d, 2H, J = 8.8 Hz, arom.), 7.20 (t, 1H, J = 7.2 Hz, arom.), 7.28 (t, 2H, J = 7.2 Hz, arom.), 7,46 (d, 2H, J = 7.2 Hz, arom.), 9,38 (s, 1H, OH), 10.27 (s, 1H, NH), 11.50 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.7, 167.3, 156.6, 138.4, 137.3, 136.6, 130.3, 129.6, 128.5, 128.3, 128.2, 128.0, 127.1, 126.7, 121.0, 120.5, 56.3, 51.1, 42.1. Anal. Calcd for C₂₅H₁₉CIN₂O₃S₂, % C, 60.66; H, 3.87; N, 5.66. Found, %: C, 60.80; H, 3.80; N, 5.80.

rel-(5R,6S,7S)-7-(4-Chlorophenyl)-N-(4-hydroxyphenyl)-2-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carboxamide (3b)

Yield: 57%, mp 220–224°C (EtOH). ¹H NMR (400 MHz, DMSO-d₆) δ: 3.44 (t, 1H, J = 10.4 Hz, 6-H), 4.28 (d, 1H, J = 10.4 Hz, 7-H), 4.68 (d, 1H, J = 10.4 Hz, 5-H), 6.47 (d, 2H, J = 8.8 Hz, arom.), 6.60 (d, 2H, J = 8.8 Hz, arom.), 7.00–7.40 (m, 7H, arom.), 7.50 (d, 2H, J = 7.2 Hz, arom.), 9,20 (s, 1H, OH), 9.83 (s, 1H, NH), 11.53 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.6, 164.5, 140.2, 139.4, 138.8, 136.3, 129.2, 128.9, 128.6, 128.3, 128.2, 128.1, 127.8, 126.9, 121.6, 114.8, 51.9, 50.8, 46.7. Anal. Calcd for C₂₅H₁₉CIN₂O₃S₂, % C, 60.66; H, 3.87; N, 5.64. Found, %: C, 60.50; H, 3.70; N, 5.70.

rel-(5R,6S,7S)-7-(4-Methylphenyl)-2-oxo-5-phenyl-N-(4-sulfamoylphenyl)-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carboxamide (3c)

Yield: 60%, mp 188–190°C (EtOH). ¹H NMR (400 MHz, DMSO-d₆) δ: 2.27 (s, 3H, CH₃), 3.95 (t, 1H, J = 11.4 Hz, 6-H), 4.47 (d, 1H, J = 11.4 Hz, 7-H), 4.73 (d, 1H, J = 11.4 Hz, 5-H), 6.98 (d, 2H, J = 7.8 Hz, arom.), 7.09 (d, 2H, J = 7.8 Hz, arom.), 7.28 (s, 2H, NH2), 7.30–7.50 (m, 5H, arom.), 7.80 (d, 2H, J = 9.0 Hz, arom.), 7.87 (d, 2H, J = 9.0 Hz, arom.), 10.49 (s, 1H, NH), 11.41 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 167.6, 163.8, 142.0, 140.9, 138.3, 136.6, 134.4, 129.9, 129.0, 127.7, 126.7, 121.7, 120.5, 118.7, 118.4, 104.8, 51.1, 42.3, 42.1, 20.7. Anal. Calcd for C₂₆H₂₃N₃O₄S₃, % C, 58.08; H, 4.31; N, 7.82. Found, %: C, 58.20; H, 4.40; N, 7.80.

rel-(5R,6S,7S)-7-(4-Chlorophenyl)-2-oxo-5-phenyl-N-(4-sulfamoylphenyl)-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carboxamide (3d)

Yield: 68%, mp 182–184°C (EtOH). ¹H NMR (400 MHz, DMSO-d₆) δ: 3.95 (t, 1H, J = 11.6 Hz, 6-H), 4.46 (d, 1H, J = 11.6 Hz, 7-H), 4.65 (d, 1H, J = 11.6 Hz, 5-H), 7.08 (d, 2H, J = 8.8 Hz, arom.), 7.27 (d, 2H, J = 8.8 Hz, arom.), 7.29 (s, 2H, NH2), 7.30–7.50 (m, 5H, arom.), 7.76 (d, 2H, J = 8.6 Hz, arom.), 7.83 (d, 2H, J = 8.6 Hz, arom.), 10.56 (s, 1H, NH), 11.55 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.0, 167.6, 163.8, 142.0, 140.9, 138.3, 130.5, 129.9, 128.9, 128.4, 127.7, 126.6, 126.5, 121.7, 118.5, 104.1, 56.0, 51.0, 42.1. Anal. Calcd for C₂₅H₂₀CIN₃O₄S₃, % C, 53.80; H, 3.61; N, 7.53. Found, %: C, 53.70; H, 3.80; N, 7.40.

rel-(5R,6S,7S)-N,7-Bis(4-chlorophenyl)-2-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carboxamide (3e)

Yield: 65%, mp 216–218°C (EtOH). ¹H NMR (400 MHz, DMSO-d₆) δ: 3.44 (t, 1H, J = 10.4 Hz, 6-H), 4.31 (d, 1H, J = 10.4 Hz, 7-H), 4.72 (d, J = 10.4 Hz, 5-H), 6.96 (d, 2H, J = 8.4 Hz, arom.), 7.03 (d, 2H, J = 8.4 Hz, arom.), 7.16–7.31 (m, 7H, arom.), 7.44 (d, 2H, J = 7.0 Hz, arom.), 9.46 (s, 1H, NH), 11.31 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.4, 168.3, 139.2, 136.4, 136.1, 132.1, 131.1, 130.1, 128.5, 128.4, 128.3, 128.2, 127.3, 121.0, 120.3, 107.4, 56.1, 48.4, 44.9. Anal. Calcd for C₂₅H₁₈CI₂N₂O₂S₂, % C, 58.48; H, 3.53; N, 5.46. Found, %: C, 58.30; H, 3.40; N, 5.50.

rel-(5R,6S,7S)-N-(4-Chlorophenyl)-7-(4-methylphenyl)-2-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carboxamide (3f)

Yield: 75%, mp 200–202°C (EtOH). ¹H NMR (400 MHz, DMSO-c/6) δ: 2.28 (s, 3H, CH₃), 3.44 (t, 1H, J = 10.4 Hz, 6-H), 4.26 (d, 1H, J = 10.4 Hz, 7-H), 4.70 (d, 1H, J = 10.4 Hz, 5-H), 6.96 (d, 2H, J = 8.8 Hz, arom.), 7.02 (d, 2H, J = 8.8 Hz, arom.), 7.05 (d, 2H, J = 7.6 Hz, arom.), 7.13 (d, 2H, J = 7.6 Hz, arom.), 7.18 (t, 1H, J = 7.2 Hz, arom.), 7.24 (t, 2H, J = 7.2 Hz, arom.), 7.44 (d, 2H, J = 7.2 Hz, arom.), 9.41 (s, 1H, NH), 11.23 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.5, 168.5, 137.2, 136.7, 136.5, 136.2, 129.0, 128.5, 128.3, 128.2, 128.1, 127.1, 119.8, 108.3, 56.2, 48.6, 45.2, 20.7. Anal. Calcd for C₂₆H₂₁CIN₂O₂S₂, % C, 63.34; H, 4.29; N, 5.68. Found, %: C, 63.50; H, 4.40; N, 5.70.

rel-(5R,6S,7S)-7-(4-Chlorophenyl)-N-(4-methylphenyl)-2-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carboxamide (3g)

Yield: 70%, mp 234–236°C (EtOH). ¹H NMR (400 MHz, DMSO-d₆) δ: 2.16 (s, 3H, CH₃), 3.44 (t, 1H, J = 10.4 Hz, 6-H), 4.30 (d, 1H, J = 10.4 Hz, 7-H), 4.70 (d, 1H, J = 10.4 Hz, 5-H), 6.75 (d, 2H, J = 8.4 Hz, arom.), 6.83 (d, 2H, J = 8.4 Hz, arom.), 7.20–7.30 (m, 7H, arom.), 7.46 (d, 2H, J = 7.2 Hz, arom.), 9.23 (s, 1H, NH), 11.29 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.4, 167.9, 139.3, 136.2, 134.9, 132.7, 132.0, 130.2, 128.6, 128.5, 128.4, 128.3, 120.4, 119.8, 119.1, 107.5, 55.8, 48.5, 45.0, 20.3. Anal. Calcd for C₂₆H₂₁CIN₂O₂S₂, % C, 63.34; H, 4.29; N, 5.68. Found, %: C, 63.20; H, 4.40; N, 5.70.

rel-(5R,6S,7S)-N,7-Bis(4-methylphenyl)-2-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carboxamide (3h)

Yield: 56%, mp 230–232°C (EtOH). ¹H NMR (400 MHz, DMSO-d₆) δ: 2.16 (s, 3H, CH₃), 2.28 (s, 3H, CH₃), 3.45 (t, 1H, J = 10.4 Hz, 6-H), 4.26 (d, 1H, J = 10.4 Hz, 7-H), 4.70 (d, 1H, J = 10.4 Hz, 5-H), 6.77 (d, 2H, J = 8.0 Hz, arom.), 6.82 (d, 2H, J = 8.0 Hz, arom.), 7.06 (d, 2H, J = 7.6 Hz, arom.), 7.14 (d, 2H, J = 7.6 Hz, arom.), 7.21 (t, 1H, J = 7.2 Hz, arom.), 7.25 (t, 2H, J = 7.2 Hz, arom.), 7.46 (d, 2H, J = 7.2 Hz, arom.), 9.18 (s, 1H, NH), 11,22 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.5, 168.1, 141.2, 140.1, 137.4, 136.6, 136.4, 135.1, 132.5, 128.9, 128.6, 128.2, 128.1, 119.8, 119.7, 108.5, 55.9, 48.7, 45.2, 20.7, 20.3. Anal. Calcd for C₂₇H₂₄N₂O₂S₂, % C, 68.62; H, 5.12; N, 5.93. Found, %: C, 68.70; H, 5.20; N, 6.00.

rel-(5R, 6S,7S)-N-(4-Chlorophenyl)-2-oxo-5-phenyl-7-(thiophen-2-yl)-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carboxamide (3i)

Yield: 84%, mp 208–210°C (EtOH). ¹H NMR (400 MHz, DMSO-d₆) δ: 3.55 (t, 1H, J = 10.5 Hz, 6-H), 4.72 (d, 1H, J = 10.5 Hz, 7-H), 4.87 (d, J = 10.5 Hz, 5-H), 6.92 (dd, 1H, J = 5.1, 3.6 Hz, thiophen.), 6.98 (d, 1H, J = 2.4 Hz, thiophen.), 7.05 (d, 2H, J = 9.0 Hz, arom.), 7.13 (d, 2H, J = 7.6 Hz, arom.), 7.17 (d, 2H, J = 8.4 Hz, arom.), 7.26 (t, 1H, J = 7.0 Hz, arom.), 7.30 (t, 2H, J = 7.5 Hz, arom.), 7.45 (d, 1H, J = 5.1 Hz, thiophen.), 7.51 (d, 2H, J = 7.2 Hz, arom.), 9.46 (s, 1H, NH), 11.31 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.3, 168.3, 142.8, 136.5, 136.0, 128.5, 128.4, 128.3, 128.2, 127.2, 126.7, 126.6, 125.8, 121.0, 119.9, 107.8, 59.6, 56.8, 48.6. Anal. Calcd for C₂₄H₂₄N₂O₃S₂, % C, 56.95; H, 3.53; N, 5.78. Found, %: C, 56.80; H, 3.70; N, 5.60.

rel-(5R,6S,7S)-7-(4-Chlorophenyl)-2-oxo-5-phenyl-N-(pyridin-2-yl)-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carboxamide (3j)

Yield: 56%, mp 178–180°C (AcOH). ¹H NMR (400 MHz, DMSO-d₆) δ: 3.48 (t, 1H, J = 10.5 Hz, 6-H), 4.24 (d, 1H, J = 10.5 Hz, 7-H), 4.84 (d, J = 10.5 Hz, 5-H), 7.16–7.45 (m, 9H, arom., pyrid.), 10.21 (s, 1H, NH), 11.50 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.7, 169.5, 150.6, 147.5, 139.2, 137.8, 136.1, 132.1, 130.3, 128.7, 128.5, 128.4, 128.3, 120.3, 119.4, 113.0, 107.5, 54.4, 48.6, 45.4. Anal. Calcd for C₂₄H₁₈CIN₃O₂S₂, % C, 60.05; H, 3.78; N, 8.75. Found, %: C, 60.10; H, 3.70; N, 8.90.

rel-(5R,6S,7S)-2-Oxo-5-phenyl-N-(pyridin-2-yl)-7-(thiophen-2-yl)-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carboxamide (3k)

Yield: 76%, mp 150–152°C (AcOH). ¹H NMR (400 MHz, DMSO-d₆) δ: 3.43 (t, 1H, J = 10.5 Hz, 6-H), 4.62 (d, 1H, J = 10.5 Hz, 7-H), 4.84 (d, J = 10.5 Hz, 5-H), 7.20–7.61 (m, 9H, arom., thiophen., pyrid.), 7.86 (d, 1H, J = 4.0 Hz, thiophen.), 8.10–8.20 (m, 2H, pyrid.), 10.29 (s, 1H, NH), 11.47 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.8, 170.4, 150.8, 147.5, 142.5, 137.7, 136.1, 134.6, 129.3, 128.7, 128.5, 128.3, 126.6, 125.9, 119.8, 113.1, 107.9, 56.1, 48.8, 47.9. Anal. Calcd for C₂₂H₁₇N₃O₂S₃, % C, 58.51; H, 3.79; N, 9.30. Found, %: C, 58.40; H, 3.90; N, 9.20.

rel-(5R,6S,7S)-7-(4-Chlorophenyl)-6-(morpholin-4-ylcarbonyl)-5-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazol-2-one (3l)

Yield: 90%, mp 206–208°C (EtOH). ¹H NMR (400 MHz, DMSO-d₆) δ: 3.44 (t, 1H, J = 10.4 Hz, 6-H), 3.45–3.55 (m, 4H, morpholin), 3.73–3.81 (m, 2H, morpholin), 4.24 (d, 1H, J = 10.4 Hz, 7-H), 4.64 (d, 1H, J = 10.4 Hz, 5-H), 7.10 (d, 2H, J = 8.0 Hz, arom.), 7.18–7.34 (m, 7H, arom.), 11.33 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.7, 166.8, 138.8, 131.8, 131.0, 128.2, 128.0, 129.9, 127.9, 127.8, 120.9, 104.6, 66.5, 66.1, 56.0, 45.3, 42.9, 41.4. Anal. Calcd for C₂₃H₂₁ClN₂O₃S₂, % C, 58.40; H, 4.47; N, 5.92. Found, %: C, 58.50; H, 4.30; N, 6.00.

rel-(5R,6S,7S)-7-(4-Methylphenyl)-6-(morpholin-4-ylcarbonyl)-5-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazol-2-one (3m)

Yield: 77%, mp 176–178°C (PhH). ¹H NMR (400 MHz, DMSO-d₆) δ: 2.33 (s, 3H, CH₃), 2.77–2.86 (m, 4H, morpholin), 2.92–2.95 (m, 2H, morpholin), 3.76 (T, 1H, J = 10.4 Hz, 6-H), 4.14 (d, 1H, J = 10.4 Hz, 7-H), 4.69 (d, 1H, J = 10.4 Hz, 5-H), 7.10 (br.s, 4H, arom.), 7.25–7.34 (m, 3H, arom.), 7.40 (d, 2H, J = 7.0 Hz, arom.), 11.25 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.5, 168.7, 146.3, 145.3, 136.9, 136.8, 128.9, 128.5, 128.3, 128.2, 120.1, 65.6, 49.2, 48.7, 45.7, 45.3, 41.3, 20.9. Anal. Calcd for C₂₄H₂₄N₂O₃S₂, % C, 58.40; H, 4.47; N, 5.92. Found, %: C, 58.30; H, 4.50; N, 5.80.

Cytotoxic Activity Against Malignant Human Tumor Cells

An anticancer in vitro assay was performed on the human tumor cell lines panel derived from nine neoplastic diseases, in accordance with the protocol of the Drug Evaluation Branch, National Cancer Institute, Bethesda [5–7, 17]. The tested compounds were added to the culture at a single concentration (10^-5 M) and the cultures were incubated for 48 h. Endpoint determinations were made with a protein binding dye, sulforhodamine B (SRB). Results for each tested compound were reported as the percent of growth of the treated cells when compared to the untreated control cells. The growth percentage was evaluated spectrophotometrically versus controls not treated with the test agents.

Acknowledgement

We thank Dr. V.L. Narayanan from the Drug Synthesis and Chemistry Branch, National Cancer Institute, Bethesda, MD, USA, for the in vitro evaluation of anticancer activity. The authors support all people of good will currently struggling for sovereign and unified Ukraine.

Authors’ Statements

Competing Interests

The authors declare no conflict of interest.

References

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[B1] 1.Lesyk RB, Zimenkovsky BS. 4-Thiazolidones: Centenarian History, Current Status and Perspectives for Modern Organic and Medicinal Chemistry. Curr Org Chem. 2004;8:1547–1577. dx.doi.org/10.2174/1385272043369773 [Google Scholar]

[B2] 2.Lesyk RB, Zimenkovsky BS, Kaminskyy DV, Kryshchyshyn AP, Havryluk DYa, Atamanyuk DV, Subtel’na IYu, Khyluk DV. Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group. Biopolym Cell. 2011;27:107–117. http://dx.doi.org/10.7124/bc.000089 [Google Scholar]

[B3] 3.Kaminskyy D, Vasylenko O, Atamanyuk D, Gzella A, Lesyk R. Isorhodanine and Thiorhodanine Motifs in the Synthesis of Fused Thiopyrano[2,3-d][1,3]thiazoles. Synlett. 2011;1385–1388. http://dx.doi.org/10.1055/s-0030-1260765 [Google Scholar]

[B4] 4.Lesyk R, Zimenkovsky B, Atamanyuk D, Jensen F, Kiec-Kononowicz K, Gzella A. Anticancer thiopyrano[2,3-d][1,3]thiazol-2-ones with norbornane moiety. Synthesis, cytotoxicity, physico-chemical properties, and computational studies. Bioorg Med Chem. 2006;14:5230–5240. http://dx.doi.org/10.1016/j.bmc.2006.03.053 [DOI] [PubMed] [Google Scholar]

[B5] 5.Boyd MR, Paull KD. Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Dev Res. 1995;34:91’109. http://dx.doi.org/10.1002/ddr.430340203 [Google Scholar]

[B6] 6.Boyd MR. In: Cancer Drug Discovery and Development. Teicher BA, ed. Volume 2, Totowa, NJ, USA: Humana Press, 1997:23–43. [Google Scholar]

[B7] 7.Shoemaker RH. The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer. 2006;6:813–823. http://dx.doi.org/10.1038/nrc1951 [DOI] [PubMed] [Google Scholar]

[B8] 8.Atamanyuk D, Zimenkovsky B, Lesyk R. Synthesis and anticancer activity of novel thiopyrano[2.3-d]thiazole-based compounds containing norbornane moiety. J Sulfur Chem. 2008;29:151–162. http://dx.doi.org/10.1080/17415990801911723 [Google Scholar]

[B9] 9.Kryshchyshyn A, Atamanyuk D, Lesyk R. Fused Thiopyrano[2,3-d]thiazole Derivatives as Potential Anticancer Agents Sci Pharm. 2012;80:509–529. http://dx.doi.org/10.3797/scipharm.1204-02 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B10] 10.Atamanyuk D, Zimenkovsky B, Atamanyuk V, Nektegayev I, Lesyk R. Synthesis and Biological Activity of New Thiopyrano[2,3-d][1,3]thiazoles Containing a Naphthoquinone Moiety. Sci Pharm. 2013;81:423–436. http://dx.doi.org/10.3797/scipharm.1301-13 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B11] 11.Zelisko N, Atamanyuk D, Vasylenko O, Grellier P, Lesyk R. Synthesis and antitrypanosomal activity of new 6,7,7-trisubstituted thiopyrano[2,3-d][1,3]thiazoles. Bioorg Med Chem Lett. 2012;22:7071–7074. http://dx.doi.org/10.1016/j.bmcl.2012.09.091 [DOI] [PubMed] [Google Scholar]

[B12] 12.Zelisko N, Atamanyuk D, Vasylenko O, Bryhas A, Matiychuk V, Gzella A, Lesyk R. Crotonic, cynnamic and propiolic acids motifs in the synthesis of thiopyrano[2,3-d][1,3]thiazoles via hetero-Diels-Alder reaction and related tandem processes. Tetrahedron. 2013;70:720–729. http://dx.doi.org/10.1016/j.tet.2013.11.083 [Google Scholar]

[B13] 13.Tomasic T, Masic LP. Rhodanine as a scaffold in drug discovery: a critical review of its biological activities and mechanisms of target modulation. Expert Opin Drug Discov. 2012;7:549–560. http://dx.doi.org/10.1517/17460441.2012.688743 [DOI] [PubMed] [Google Scholar]

[B14] 14.Lau J, Jeppsen C, Rimvall K, Hohlweg R. Ureas with histamine H₃-antagonist receptor activity- A new scaffold discovered by lead-hopping from cinnamic acid amides. Bioorg Med Chem Lett. 2006;16:5303–5308. http://dx.doi.org/10.1016/j.bmcl.2006.07.093 [DOI] [PubMed] [Google Scholar]

[B15] 15.Shukla Y, Srivastava A, Kumar S, Kumar S. Phytotoxic and antimicrobial constituents of Argyreia speciosa and Oenothera biennis. J Ethnopharmacol. 1999;67:241–245. http://dx.doi.org/10.1016/S0378-8741(99)00017-3 [DOI] [PubMed] [Google Scholar]

[B16] 16.Narasimhan B, Belsare D, Pharande D, Mourya V, Dhake A. Esters, amides and substituted derivatives of cinnamic acid: synthesis, antimicrobial activity and QSAR investigations. Eur J Med Chem. 2004;39:827–834. http://dx.doi.org/10.1016/j.ejmech.2004.06.013 [DOI] [PubMed] [Google Scholar]

[B17] 17.Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, Gray-Goodrich M, Campbell H, Mayo J, Boyd M. Feasibility of a High-Flux Anticancer Drug Screen Using a Diverse Panel of Cultured Human Tumor Cell Lines. J Nat Cancer Inst. 1991;83:757–766. http://dx.doi.org/10.1093/jnci/83.11.757 [DOI] [PubMed] [Google Scholar]

PERMALINK

Synthesis and Anticancer Activity of New Thiopyrano[2,3-d]thiazoles Based on Cinnamic Acid Amides

Andrii Lozynskyi

Borys Zimenkovsky

Roman Lesyk

Abstract

Introduction

Sch. 1.

Results and Discussion

Chemistry

Sch. 2.

Biological Activity

Tab. 1.

Sch. 3.

Experimental

Chemistry

General Procedure of the Hetero-Diels-Alder Reaction Affording 3a-m

Cytotoxic Activity Against Malignant Human Tumor Cells

Acknowledgement

Authors’ Statements

Competing Interests

References

ACTIONS

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PERMALINK

Synthesis and Anticancer Activity of New Thiopyrano[2,3-d]thiazoles Based on Cinnamic Acid Amides

Andrii Lozynskyi

Borys Zimenkovsky

Roman Lesyk

Abstract

Introduction

Sch. 1.

Results and Discussion

Chemistry

Sch. 2.

Biological Activity

Tab. 1.

Sch. 3.

Experimental

Chemistry

General Procedure of the Hetero-Diels-Alder Reaction Affording 3a-m

Cytotoxic Activity Against Malignant Human Tumor Cells

Acknowledgement

Authors’ Statements

Competing Interests

References

ACTIONS

PERMALINK

RESOURCES

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