Synthesis and evaluation of 5-(1 H -indol-3-yl)- N -aryl-1,3,4-oxadiazol-2-amines as Bcl-2 inhibitory anticancer agents

Abstract

A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a-j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin. Active compounds of the series 8a-j were found to have sub-micromolar IC values selectively in Bcl-2 expressing human cancer cell lines; notably the 2-nitrophenyl analogue 8a was found to exhibit potent activity, and compounds 8a and 8e possessed comparable Bcl-2 binding affinity (ELISA assay) to the established natural product-based Bcl-2 inhibitor, gossypol. Molecular modeling studies helped to further rationalise anti-apoptotic Bcl-2 binding, and identified compounds 8a and 8e as candidates for further development as Bcl-2 inhibitory anticancer agents.

New Indolyl‐Arylaminopropenone Conjugates: Synthesis, Cytotoxicity and Apoptotic Inducing Studies

“…Bcl‐2 (B cell lymphoma 2) family of anti‐apoptotic proteins are vital proteins expressed during apoptosis. They also tend to promote the resistance of cancer cells to the available chemotherapeutic drugs . Efforts are being made towards the development of Bcl‐2 inhibitory anticancer agents .…”

New Quinoline-Based Heterocycles as Anticancer Agents Targeting Bcl-2

“…Evaluation of anti-proliferative activity for the new quinolin-4-yl- N -aryloxadiazol-2-amines ( 6a–k ) and quinolin-4-yl-benzoylmethylthiotriazoles ( 8a–b ) was carried out in established MDA-MB-231 (metastatic breast) and HeLa (cervical) cancer cell lines using the MTT endpoint assay, according to methodology previously described by our group and others [5,6]. MDA-MB-231 and HeLa are Bcl2-expressing cancer cell lines where Bcl-2 inhibitory molecules have shown protein down-regulation following treatment [13,14].…”

“…Additionally, to test the effect of differing cellular Bcl-2 status, compounds 6a–k and 8a–b were evaluated for activity in the leukaemic cell lines KG1a (acute myelogenous leukaemia, Bcl-2 positive, [15]) and Jurkat (T-cell leukaemia, Bcl-2 negative, [16]). As previously described [5,6], for the studies in the leukaemic cell lines we used the CellTitreBlue® endpoint assay, appropriate for testing anti-proliferative activity in these non-adherent cells.…”

“…Our own work has led to the early stage design and discovery of indole-based heterocycles as new Bcl-2 inhibitors based on a molecular modelling and virtual screening approach to identify hit molecules. We have previously reported on series of 3-(benzylthio)-5-(indol-3-yl)-1,2,4-triazol-4-amines, 5-(indol-3-yl)- N -aryl-[1,3,4]-oxadiazol-2-amines and 5-(indol-3-yl)-2-[(2-nitrophenyl)amino][1,3,4]-oxadiazole as Bcl-2 inhibitory anticancer agents (Figure 1) [5,6,7]. In this study, we further explore structure-activity relationships around this heterocyclic framework and synthesise further novel nitrogen-containing aromatic heterocycles for characterisation and biological testing, focusing on the corresponding quinoline derivatives.…”

Synthesis, Biological Evaluation and Molecular Docking of Novel Curcumin Derivatives as Bcl‐2 Inhibitors Targeting Human Breast Cancer MCF‐7 Cells

“…In terms of development of new cancer therapeutics, small molecule anti‐apoptotic Bcl‐2 inhibitors offer exciting prospects . Bcl‐2 is the first apoptosis‐related gene acknowledged to play a significant role in tumerogenesis and is overexpressed in a range of cancers and it appears to be actively involved in the regulation of apoptosis and proliferation of human breast cancer cells …”