Design, Synthesis and Biological Evaluation of 2-Anilinopyridyl-Linked Oxindole Conjugates as Potent Tubulin Polymerisation Inhibitors

Abstract

A series of 2‐anilinopyridyl linked oxindole conjugates (6 a‐ad) were synthesized andevaluated for their antiproliferative activity against a panel of four human cancer cell lines viz., HeLa, DU‐145, A549 and MCF‐7. All the compounds showed very good to moderate anticancer activity against the tested cell lines. Amongst the series, conjugates 6 h, 6 q, 6 r, 6 s and 6 y exhibited promising antiproliferative activity with IC50 values ranging between 0.7 to 1 μM selectively against human prostate cancer cell line (DU‐145). Interestingly conjugate 6 r was twice more potent than E7010 and the flow cytometric analysis revealed that 6 r and 6 y induced cell cycle arrest at G2/M phase. Treatments with 6 r and 6 y manifested increased protein levels of the G2/M marker, cyclin B1. Tubulin polymerization inhibition assay, competitive colchicine binding assay and western blot analysis suggested that they inhibit microtubule assembly formation. Immunocytochemistry revealed loss of intact microtubule structure in cells treated with 6 r and 6 y. In addition, Hoechst staining and mitochondrial membrane depolarisation assay results further support induction of apoptosis by these conjugates leading to cell death. Molecular docking studies is suggestive of that these conjugates occupy the colchicine binding site of the tubulin and could be considered as potential leads with antiproliferative activity.

A Review of the Recent Developments of Molecular Hybrids Targeting Tubulin Polymerization

“…The design, synthesis, and evaluation of a series of anilinopyridyl-oxindole hybrids ( 178 ) against a panel of four human cancer cell lines have been reported [ 150 ]. Interestingly, the evaluated compounds displayed good to moderate anti-cancer activity against the tested cell lines, namely, HeLa, DU-145, A549, MCF-7, and normal rat kidney cell lines (NRK-49F), respectively.…”

Isatin and its derivatives: a survey of recent syntheses, reactions, and applications

“…The molecular docking study of 29r and 29y at the colchicine binding site of tubulin (PDB ID: 3HKC) highlighted that these compounds fit well at the α-β interface of the protein. 73 The 5,7-dibromoisatin analogs (30) have been evaluated as dual inhibitors of tubulin polymerization and the Akt pathway. Among these, compounds 30d and 30e inhibited tubulin polymerization to the same extent as the anti-cancer drug vinblastine sulfate, whereas significantly better activity than vinblastine sulfate has been reported for compounds 30j and 30l.…”

In Silico Exploration of Novel Tubulin Inhibitors: A Combination of Docking and Molecular Dynamics Simulations, Pharmacophore Modeling, and Virtual Screening

“…Despite the progress in the administration of microtubule targeting agents for the treatment of patients with cancer, currently, there are no FDA-approved tubulin inhibitors targeting the colchicine binding site [9]. This has encouraged medicinal chemists to design and discover the novel antimitotic agents that bind to the colchicine binding site for cancer therapy [10][11][12][13][14][15][16].…”