Abstract
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.
Highlights
1,4,2-Benzodithiazines are very attractive lead structures for designing new compounds as potential pharmaceutical agents
We have developed a facile method for the synthesis of new 3-amino-6-chloro-7-(azol-2 or 5-yl)-1,1-dioxo-1,4,2-benzodithiazine derivatives
The best antiproliferative properties have been observed for compound 5h, especially against the ovarian (OVCAR-3) and breast (MDA-MB-468) cancer cell lines
Summary
1,4,2-Benzodithiazines are very attractive lead structures for designing new compounds as potential pharmaceutical agents. Of particular interest is that much research on the use of 6-chloro-1,1-dioxo-1,4,2-benzodithiazines as potential therapeutic agents has demonstrated that some of them exhibit remarkable anticancer activity (Figure 1, I [11,12,13,14], II, III [13,15,16] and IV [17]) With regard to these reports we have designed novel benzodithiazine derivatives of the general structure of type V (Figure 1) that vary according to both the nitrogen-containing 5-membered heterocycle scaffold at position 7 and the substituent bearing either a condensed indazole or indole ring attached to the amine group at position 3 of the 6-chloro-1,1-dioxo-1,4,2-benzodithiazine ring. Toinfovocerosirgtriigenal.ateTtedotcfhooerrrciehnleavmtietirctohaalecscttihrvueitmcytuiacrgaelaoisnftrscutoc6mt0uprhoeuuomnfadcnsomwcapintohceutrnhcdeeisrllwpliointtheesnthcfryeoimtropidonithfefienbrcietynttthooeirgngrhaonibwsitohtfhoef gcaronowcreigtrhicnoe. lfTlscoaqcnuocarernretlciatetaeltlistvhqeeuscathrneutmicttaiuctarivel -esatrscutricvutiucttryuerroeefl-aactocitmoinvpsiothyuipnred(lQsawtSiAoitnhRs)thhaiepniar(lQpyosStiAesnRwc)yaastnoaapilnpyhlsiiibesditw.tAhases agaprropewlsiutehldto,. ftAhse amroecsastunclitem,rtpcheoelrlmtsaqnoustat npimtaitrpaatomirvteeatsentrtrsupcactrouanrmetr-eaotcleltiirnvsigtcyotrnhetelraotbliloiionnlsgohgtiphice(aQlbSipoAlroRogp) iaecnratalilepysrsoishpawevraetsieabspehpealniveded.beAetesernamrdienesteuedlrtm, uthisneiendg ustsaimtnigsotsistctailtmiaspptiopcrartloaanpcthppersao.raacmheeste. rs controlling the biological properties have been determined using statistical approaches
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