Towards breast cancer targeting: Synthesis of tetrahydroindolocarbazoles, antibreast cancer evaluation, uPA inhibition, molecular genetic and molecular modelling studies.

A series of some new tetrahydroindolocarbazole derivatives has been synthesized. The structure of the synthesized compounds has been confirmed by different spectroscopic techniques such as IR, NMR, elemental analysis and mass spectrometry. The target compounds were evaluated for their antitumor activity against breast cancer cell line MCF-7, their GI% and their LC50 have been determined. Six of the synthesized compounds exhibited GI% values against MCF-7 cell lines exceeding 70% ranging from 71.9 to 85.0% in addition that compound 11 expressed GI% values of 99.9% and considered the most active derivatives among the synthesized ones. Compound 11 showed a remarkable decrease of u PA level to 3.5 ng/ml compared to DOX. Compound 5, 11 and 15 showed significant decrease in expression of MTAP and CDKN2A, in addition to a remarkable decrease in DNA damage comet assay method. Molecular modeling studies were performed to interpretate the behavior of active ligands as uPA inhibitors.

Novel dihydropyridine thioglycosides and their corresponding dehydrogenated forms as potent anti-hepatocellular carcinoma agents.

A novel method for preparation of a new class of dihydropyridine thioglycosides and their corresponding dehydrogenated forms, via reaction of piperidinium salts of dihydropyridinethiones with 2,3,4,6-tetra-O-acetyl-α-D-gluco- and galactopyranosyl bromides has been studied. The evaluation of antiproliferative activity against HepG-2 cell lines (liver carcinoma cell lines) of the dihydropyridine thioglycosides and pyridine thioglycosides revealed that many of the thioglycosides have interesting antitumor activities specifically 5c, 5g, 5l, 5o, 5p, 7a, 7i, 7p, 8b, 8f, 8s, and 8v.

One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a-p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC50 = 6.70, 6.40 and 6.70 µM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 120 and 150 nM, respectively). Collectively, these data demonstrated that 6e might be a potential lead compound for the development of effective anti-TNBC agents.