The isothiocyanate derivatives six and 13 had been synthesized from the remedy of 5,7-dibromoisatin with tert-butyl 3-bromopropylcarbamate or tert-butyl carbamate inside the presence of K2CO3 in DMF, to afford Boc-protected intermediates 14 and 15, respectively. The Boc group in 14 and 15 was removed by trifluroacetic acid, followed by a response with thiophosgene with K2CO3 in anhydrous methylene chloride to offer six and 13 in superior yield. All of these compounds had been purified by column chromatography or recrystallization and dried below substantial vacuum. The purity with the compounds was examined by HPLC, Y 99% pure compounds were applied for biological assays . The cytotoxicity of the series of new N-alkyl derivatives of five,7-dibromoisatin was evaluated against a panel of 4 numerous human cancer cell lines which include a colon , breast , lung and melanoma , following a constant exposure of 48h. The results are summarized in Table one.
Each of the compounds exhibited sizeable cytotoxicity with an IC50 values of <5 |ìM in HT29 cell line; compounds 6, 11 and 13 showed relatively higher potency with IC50 values of 1.56, 1.14 and 1.09 |ìM, respectively. The results showed that the cytotoxicity of compound 2 significantly increased through N-alkylation, as reported previously for the 5,7- dibromoisatin derivatives17. Compounds 3¨C6, selleck chemical pf-562271 contain a three-carbon linker, compounds 7¨C9 contain a four-carbon linker, and compounds 10¨C13 contain an aromatic ring with a onecarbon linker at the nitrogen N1. The findings showed that, by slightly increasing the hydrophobicity, there is no significant change in the inhibiting activity between N-butyl series and N-propyl series . Introduction of N-benzyl with isothiocyanate/thiocyanate groups to the alkyl chain yielded relatively more active compounds in this series against the growth of HT29 colon cancer cells.
The MCF-7 cell line was susceptible to compounds five, 9 and 12 with IC50 values of one.65, one.53 and one.45 |ìM, respectively. All other compounds were significantly less potent against MCF-7 cells. This result could be due in part to the expression in the anti-apoptotic Bcl-2 XL765 group of proteins which have been recognized in MCF-7 cells48¨C51. Substitution of SeCN group within the alkyl chain , showing higher inhibitory exercise in contrast to the other compounds against MCF-7 cells, signifies that selenium may be taking part in a part within the antiproliferative exercise presumably through the inhibition of anti-apoptotic Bcl-2 group of proteins. These selenium substituted compounds also showed good inhibitory activity against HT29 and A549 cell lines, but bad inhibitory exercise in UACC903 cells.
ITCs and thiocyanates didn’t diminish the cytotoxic action towards the MCF-7 cell lines, but have been alot more potent in colon and lung cancer cell lines. Selenium compounds were more potent than corresponding sulfur containing compounds in killing MCF-7 cells.