Novel 3-Amino-6-chloro-7-(azol-2 or 5-yl)-1,1-dioxo-1,4,2-benzodithiazine Derivatives with Anticancer Activity: Synthesis and QSAR Study.

A series of new 3-amino-6-chloro-7-(azol-2 or 5-yl)-1,1-dioxo-1,4,2-benzodithiazine derivatives 5a-j have been synthesized and evaluated in vitro for their antiproliferative activity at the U.S. National Cancer Institute. The most active compound 5h showed significant cytotoxic effects against ovarian (OVCAR-3) and breast (MDA-MB-468) cancer (10% and 47% cancer cell death, respectively) as well as a good selectivity toward prostate (DU-145), colon (SW-620) and renal (TK-10) cancer cell lines. To obtain a deeper insight into the structure-activity relationships of the new compounds 5a-j QSAR studies have been applied. Theoretical calculations allowed the identification of molecular descriptors belonging to the RDF (RDF055p and RDF145m in the MOLT-4 and UO-31 QSAR models, respectively) and 3D-MorSE (Mor32m and Mor16e for MOLT-4 and UO-31 QSAR models) descriptor classes. Based on these data, QSAR models with good robustness and predictive ability have been obtained.

Carbonic anhydrase inhibitors. Synthesis of a novel series of 5-substituted 2,4-dichlorobenzenesulfonamides and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII.

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).

Synthesis and in vitro activity of novel 2-(benzylthio)-4-chloro-5-(1,3,4-oxadiazol-2-yl)benzenesulfonamide derivatives.

ABSTRACT: Two series of novel 4-chloro-2-(benzylthio)-5-(1,3,4-oxadiazol-2-yl)benzenesulfonamides and their N-aroyl derivatives have been synthesized and evaluated for in vitro anticancer activity against the full NCI-60 cell line panel. Most of the compounds exhibited antiproliferative activity. Among them a compound bearing an N-(thien-2-ylcarbonyl) moiety showed broad-spectrum activity with 50% growth inhibition (GI50) values in the range of 2.02-7.82 µM over 50 cell lines. GRAPHICAL ABSTRACT: .

1-(2-Mercaptobenzenesulfonyl)-3-hydroxyguanidines--novel potent antiproliferatives, synthesis and in vitro biological activity.

Twenty four 1-[2-alkylthio-5-(azol-2 or 5-yl)-4-chlorobenzenesulfonyl]-3-hydroxyguanidines 6a-x have been synthesized in order to evaluate their biological activity. Compounds 6a, 6c, 6d, 6f, 6g, 6i-p, 6r-t, and 6v-x were tested for their in vitro anticancer activity at the US National Cancer Institute. The highest in vitro anticancer activity was found for compounds 6d, 6g and 6k with GI(50) average value in the range 1.62-1.86 µM, and TGI mean values 3.72-4.47 µM, whereas the remaining compounds showed broad spectrum of anticancer activity at low micromolar GI(50) level against all tested cancer cell lines. These results were subjected to CoMSIA analysis to establish quantitative structure-activity relationships. The results evidence that potency of these compounds correlates mainly with hydrophobic and polar surface properties of substituents located both at 2 and 5 positions of 1-(4-chlorobenzenesulfonyl) moiety of investigated 3-hydroxyguanidine series.