Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity (original) (raw)
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Heterocyclic Communications, 2006
The preparation of novel 3,4-dihydro-2//-l,2,4-benzothiadiazine-l,l-dioxide derivatives through the condensation of halogenated 2-aminobenzenesulfonamides and benzaldehydes using sodium hydrogen sulfite is described. Contrary to previous reports for non substituted 2aminobenzenesulfonamides, sodium hydrogen sulfite does not effect the dehydrogenation of 3,4-dihydro compounds to the corresponding 3,4-unsaturated 2//-l,2,4-benzothiadiazines. The preliminary cytotoxic evaluation of some of these new compounds toward several human tumor cell lines is also reported.
Mitochondrial complex II (CII) is an emerging target for numerous human diseases. Sixteen analogues of the CII inhibitor natural product atpenin A5 were prepared to evaluate the structure– activity relationship of the C5 pyridine side chain. The side chain ketone moiety was determined to be pharmacophoric, engendering a bioactive conformation. One analogue, 1-(2,4-dihydroxy-5,6-dimethoxypyridin-3-yl)hexan-1-one (16c), was found to have a CII IC50 value of 64 nm, to retain selectivity for CII over mitochondrial complex I (>156-fold), and to possess a ligand-lipophilicity efficiency (LLE) of 5.62, desirable metrics for a lead compound. This derivative and other highly potent CII inhibitors show potent and selective anti-proliferative activity in multiple human prostate cancer cell lines under both normoxia and hypoxia, acting to inhibit mitochondrial electron transport.
Cogent Chemistry
In this study, we designed and synthesized a series of 1,4-benzothiazine and evaluated them for anticancer activity toward HT-29 human colon cancer cells using SRB assay. Before the synthesis, docking studies were performed using various molecular targets of colon cancer including IL-2, IL-6, COX-2, caspase-3, and caspase-8. The molecular dynamic (MD) simulation was also executed to examine the stability of ligand-receptor complex of more stable dock conformation. Further computational study was carried out in order to predict the pharmacokinetic profile of titled compounds. Among 34 tested compounds, compounds AR13 and AR15 were found to be active against HT-29 cells (GI 50 < 10 μM). Moreover, Compounds AR5, AR22, and AR34 showed the moderate activity with GI 50 < 70 μM. The binding energy was found to be > −5 kcal/mol for AR13 and AR15 with all the molecular targets and the ligand-protein complex was found stable after its formation. Again, computational analysis revealed that both molecules AR13 and AR15 had good ADMET profiling. These encouraging outcomes allowed us to conclude that both AR13 and AR15 may emerge as lead compounds against colon cancer.
Synthesis, reactions, and biological activity of 1,4-benzothiazine derivatives
Monatshefte Fuer Chemie Chemical Monthly, 2010
6,7-Dimethoxy-2H-1,4-benzothiazin-3(4H)-one reacts with dimethylformamide dimethylacetal (DMF-DMA) to give the novel enaminone 2-(dimethylaminomethylene)-6,7-dimethoxy-2H-1,4-benzothiazin-3(4H)-one. The reaction of the latter with various active methylene compounds afforded pyrido[3,2-b][1,4]benzothiazines. Also, coupling of the enaminone with diazotized aniline derivatives gave 2-(arylhydrazono)-6,7-dimethoxy-2H-1,4-benzothiazin-3 (4H)-ones. Spectral data indicated that the latter compounds exist predominantly in the hydrazone tautomeric form. In addition, coupling of the enaminone with diazotized heterocyclic amines afforded tetra-and pentaheterocyclic ring systems. The antitumor and antimicrobial activity of some of the synthesized compounds was screened.
Arkivoc, 2004
In this work we describe the synthesis and the biological activity of 2-[(E)-3-(6chloroimidazo[2,1-b]thiazol-5-yl)prop-2-enyl]-5,6-dimethoxy-3-methyl-1,4-benzoquinone i.e. an imidazothiazole derivative connected to the benzoquinone ring of Q 0 . This compound was tested as specific inhibitor of the NADH:ubiquinone (UBQ) reductase activity of NADH dehydrogenase in mitochondrial membranes. Binding of the imidazothiazole moiety to the quinone site normally occupied by the isoprenoid lateral side chain increases the inhibitory effect (with an IC 50 for NADH-Q 1 activity of 0.24 µM) whereas the benzoquinone moiety seems to lose the capability as electron acceptor from Complex I. The new compound was also tested as potential antitumor agent at the National Cancer Institute.
Medicinal Chemistry, 2011
A practical synthesis of 2,3-diarylated 2H-benzo[e][1,2]thiazine 1,1-dioxides and their 3,4-dihydro derivatives was developed. ortho-Methyl lithiation of N-aryl-o-toluenesulfonamide followed by reaction with aryl aldehydes gave carbinol sulfonamides, which were either converted directly, or first oxidized to their ketones and converted, to 2,3-diarylated six-membered benzosultams via a TMSCl-NaI-MeCN mediated cyclization. A library of benzosultams was synthesized and evaluated for inhibitory activity against MCF-7 cells. Compound 3 in the 3,4-dihydro (saturated) series and compound 8 in the unsaturated series exhibited the highest potencies with growth inhibition (GI50) values of 0.8 and 18.0 μM, respectively. Molecular modeling studies suggest that these compounds can associate with the colchicine binding site on microtubules. However, experimental assessments of that and other mechanistic possibilities are still ongoing.