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A bstract A series of new N'-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-1-(5-phenyl-1H-pyrazol-1-yl)amidine derivatives have been synthesized and evaluated in vitro by MTT assays for their antiproliferative activity against cell lines of colon cancer HCT-116, cervical cancer HeLa and breast cancer MCF-7. The studied compounds display selective activity mainly against HCT-116 and HeLa cells. Thus, five compounds show selective cytotoxic effect against HCT-116 (IC50 = 3–10 μM) and HeLa (IC50 = 7 μM). Importantly, the noticed values of IC50 for four compounds are almost 4-fold lower for HeLa than non-malignant HaCaT cells. More-in-depth biological research revealed that the treatment of HCT-116 and HeLa with active compound resulted in increased numbers of cells in sub-G1 phase in a time dependent manner, while non-active derivative does not influence cell cycle. Metabolic stability assays using liver microsomes and NADPH provide important information on compounds susceptibility to phase 1 biotransformation reactions.

A new series of N-(aryl/heteroaryl)-2-chlorobenzenesulfonamide derivatives 4-21 have been synthesized, and evaluated at the National Cancer Institute (USA) for their in vitro activities against a panel of 60 different human cancer cell lines. Among them, compounds 16, 20 and 21 exhibited remarkable cytotoxic activity against numerous human cancer cell lines. We found that sulfonamide derivative 21 appeared to be more selective than compounds 16 and 20. In comparison to compounds 16 and 20 it showed higher cytotoxic activity against A549 non-small cell lung adenocarcinoma and HCT-116 colon carcinoma cells and was less toxic to HEK-293 human embryonic kidney cells and HaCaT immortalized human keratinocytes. Treatment of A549 and HCT-116 cells with compound 21 resulted in the G0/G1-cell cycle arrest with a concomitant increase in p53 and p21 protein levels. Moreover, compound 21 led to ATP depletion and disruption of the mitochondrial membrane potential in both studied cell lines. Our results suggest that 2,4-dichloro-N-(quinolin-8-yl and/or 1H-indazol-7-yl)benzenesulfonamides serve as novel promising anticancer agents.

A series of novel N 4 -substituted 4-(2-aminoethyl)benzenesulfonamides 5 – 17 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is the cytosolic CA I and II, and tumor-associated isozymes CA IX and XII. Against the human CA I investigated compounds displayed K I values from 96.3 to 3520 nM, toward hCA II at range of 18.1–2055 nM, while against hCA IX ranging from 5.9 to 419 nM and against hCA XII in the range of 4.0–414 nM. The very good inhibitory activity against tumor-associated hCA IX and hCA XII was found. The six new compounds displayed a powerful inhibitory potency toward hCA IX ( K I = 5.9–10.7 nM) in comparison with the clinically used CAIs AAZ , MZA , EZA , DCP and IND (24–50 nM). The most potent hCA IX and hCA XII inhibitors 11 and 12 ( K I : 5.9 and 6.2 nM for hCA IX and 4.3 and 4.0 nM for hCA XII, respectively) belonged to the compounds with cationic character and presented meaningful affinity to the transmembrane isoforms hCA IX and XII than to physiologically dominant isozymes hCA I and II with the selectivity ratios hCA IX versus hCA II and hCA XII versus hCA II for 11 and 12 in the range of 10–15.

A series of novel 5-substituted 2,4-dichlorobenzenesulfonamides 5a–c, 6a–d, 7a–j and 10a–i have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and tumor-associated isozymes CA IX and XII. Against the human CA I investigated compounds displayed KI values from 349 to 7355 nM, toward hCA II at range of 6.9 to 164 nM, while against hCA IX ranging from 2.8 to 76 nM and against hCA XII in the range of 2.7 to 95 nM. The excellent inhibitory activity against tumor-associated hCA IX was found. The twenty one new compounds displayed a powerful inhibitory potency toward hCA IX (KI = 2.8–21.7 nM) in comparison with the clinically used CAIs AAZ, MZA, EZA, DCP and IND (24–50 nM). Among them the most potent hCA IX inhibitor 7b (KI = 2.8 nM) was 8.5-fold stronger than IND (KI = 24 nM). Toward tumor-associated hCA XII compounds 6c and 10a (KI = 2.7 and 2.8 nM, respectively) showed a better inhibitory potency than reference sulfonamides MZA and IND (KI = 3.4 nM).

A series of novel heterocyclic 4-substituted pyridine-3-sulfonamides 2–13, 15–20 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and tumor-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed KI values in the range 169–5400 nM, toward hCA II in range 58.5–1238 nM, against hCA IX in range 19.5–652 nM and against hCA XII in the range of 16.8–768 nM. Compounds 15–19 representing 4-(1H-pyrazol-1-yl)-3-pyridinesulfonamide derivatives showed good hCA IX inhibitory efficacy with KI = 19.5–48.6 nM comparable or more effective than clinically used sulfonamides: AAZ, MZA, EZA, DCP, IND (KI = 24–50 nM). Anticancer evaluation at a single dose 10 μM, against a panel of 60 human tumor cell lines, was performed at the US National Cancer Institute, on compounds 2, 3, 5–13, 16, 17, 19, 20. Among them 6 bearing 4-(3,4,-dichlorophenyl)piperazine moiety showed broad spectrum of growth inhibition in the range 25–89% over 26 cell lines representing all tumors subpanels.

3-Amino-1,1-dioxopyrido[4,3- e ]-1,4,2-dithiazine has been synthesized and applied to the synthesis of 3-amino-2-(4-thioxo-1,4-dihydropyridin-3-ylsulfonyl)guanidine. The reaction of the aminoguanidine with the appropriate 1,2-diarylethane-1,2-diones afforded 2,3-diaryl-9,9-dioxo-1 H -9-thia-1,4,4a,7,10-pentaazaphenanthrene-2-ol derivatives. The structure of these compounds, which represent a novel heterocyclic ring system, was confirmed on the basis of elemental analysis and spectroscopic data including COSY, NOESY, ROESY, HSQC, and HMBC.

A series of novel 3-pyridinesulfonamide derivatives (2-5, 9-11 and 13-15) have been synthesized and investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic ubiquitous CA I and II, and isozymes CA IX and XII (cancer-associated), and XIV. Against the human isozyme hCA I the new compounds showed K(I)s in the range of 0.089-251 μM, whereas toward hCA II, K(I)s = 50.5-487 nM. Isozyme hCA IX was inhibited with K(I)s in the range of 5.2-18.3 nM, while hCA XII with K(I)s = 6.0-16.4 nM, and hCA XIV with K(I)s = 76.4-152.0 nM. All of the new compounds 2-5, 9-11 and 13-15 showed excellent hCA IX inhibitory efficacy, with K(I)s = 5.2-18.3 nM, being much more effective as compared to the clinically used AAZ, MZA, EZA, DCP and IND (K(I)s = 24-50 nM).

A new series of N -(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides 23 – 48 have been synthesized as potential anticancer agents. All compounds were screened for their cytotoxic activity against six human tumor cell lines. The selected compounds 23 – 27 , 30 , 31 , 33 , 35 , 38 , 42 , 45 , and 46 were further tested at the US National Cancer Institute for their in vitro activities against a panel of 53–59 human tumor cell lines. The compounds 23 – 26 , 30 , 31 , 33 , 38 , 42 , 45 , and 46 showed 50% growth inhibitory activity in low micromolar concentration (GI 50 = 0.03–4.9 μM) against one or more human tumor cell lines ( Table 3 ). The prominent compound with remarkable activity (GI 50 = 0.03 μM, TGI = 1.3 μM) and selectivity toward melanoma UACC-257 cell line was N -(6-chloro-7-cyano-1,1-dioxo-1,4,2-benzodithiazin-3-yl)- N -(phenyl)-5-bromothiophene-2-sulfonamide 46 .

Three series of novel 2-benzylthio-4-chloro-5-R1-benzenesulfonamides bearing the N-(benzoxazol-2-yl) (10–19), N-(benzothiazol-2-yl) (20–21) or N-(1,3-dihydro-2H-benzimidazol-2-ylidene) (22–25) moiety were synthesized by reacting N-(2-benzylthio-4-chloro-5-R1-benzenesulfonyl)cyanamide potassium salts (5–9) with 2-aminophenols, 2-aminothiophenol and o-phenylenediamines, respectively. Compounds with carbamoyl substituent at position 5 (14–16, 21 and 25, R1 = CONH2) were further dehydrated to the corresponding nitriles (26–30, R1 = CN). The in vitro antitumor activity of the compounds obtained was determined at the National Cancer Institute (NCI), and the structure–activity relationships were discussed. N-(2-benzoxazolyl)-2-benzylthio-4-chloro-5-(4-fluorophenylcarbamoyl)benzenesulfonamide (18) is the prominent of the compounds due to its remarkable activity and selectivity toward non-small cell lung cancer (NCI-H522) and melanoma (SK-MEL-2) cell lines (GI50 = 0.1 μM, TGI = 0.5–0.6 μM).

The syntheses of S-(5-chloro-4-methyl-2-sulfamoylphenyl)alkanethio (or benzothio)hydrazonates (3a-3o) and potassium S-(5-chloro-2-cyanoamidatesulfonyl-4-methylphenyl)alkanethio (or benzothio)hydrazonates (4-10) are described. The compounds 3e, 3i-3o, 7 and 8 were screened at the National Cancer Institute (NCI) for their activities against a panel of 59 tumor cell lines and relationships between structure and antitumor activity in vitro are discussed. The compounds 3e, 3j, 3l-3o and 7 exhibited reasonable activity against numerous human tumor cell lines. The prominent compound 3l showed significant activity against some cell lines of leukemia (SR), melanoma (SK-MEL-5), CNS cancer (SF-539), ovarian cancer (OVCAR-3, OVCAR-4) and breast cancer (MDA-MB-231/ACTT) (GI50 values in the range 0.3-0.9 microM). Furthermore, compound 8 exhibited the high selectivity against renal cancer (A498) cells (GI500.01 microM, TGI = 2.3 microM and LC50 = 35.7 microM).