Cytotoxic substituted indolizines as new colchicine site tubulin polymerisation inhibitors

Abstract

A potential microtubule destabilising series of new indolizine derivatives was synthesised and tested for their anticancer activity against a panel of 60 human cancer cell lines. Compounds 11a, 11b, 15a, and 15j showed a broad spectrum of growth inhibitory activity against cancer cell lines representing leukaemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast, and prostate. Among them, compound 11a was distinguishable by its excellent cytostatic activity, showing GI 50 values in the range of 10-100 nM on 43 cell lines. The less potent compounds 15a and 15j in terms of GI 50 values showed a high cytotoxic effect against tested colon cancer, CNS cancer, renal cancer and melanoma cell lines and only on few cell lines from other types of cancer. In vitro assaying revealed tubulin polymerisation inhibition by all active compounds. Molecular docking showed good complementarity of active compounds with the colchicine binding site of tubulin.

Synthesis and Biological Screening of New Cyano-Substituted Pyrrole Fused (Iso)Quinoline Derivatives

“…Thus, the isoquinoline moiety overlapped with the trimethoxysubstituted ring of phenstatin, being stabilized exclusively through hydrophobic interactions with side chains mainly in the β subunit (βCys241, βLeu255, βLeu242, βAla250, βLeu248, αAla180). This has been previously seen with other heterocyclic compounds possessing low anticancer activity, yet ability to inhibit tubulin polymerization in vitro [ 17 ]. Quinolines 5a – c spanned the dimer interface by anchoring to βAsn258 and engaging in hydrophobic contacts with fewer β subunit side chains when compared to more active compounds ( Table 6 ).…”

“…Taking into account the abovementioned details, as well as our ongoing interest in developing new bioactive fused heterocycles [ 17 , 18 , 19 , 20 , 21 , 22 ], we present herein the design and synthesis of novel pyrrolo[1,2- a ]quinoline and pyrrolo[2,1- a ]isoquinoline derivatives which show great promise as anticancer agents. The compounds bear cyano- and 4-substituted phenacyl groups as substituents at the pyrrole ring.…”

Discovery of indolizine lactones as anticancer agents and their optimization through late-stage functionalization

“…2). The presence of alkoxylated motifs in a series of natural and synthetic compounds with observed antitumoral activities 21,[33][34][35][36] and in other studies with indolizine derivatives as well, 10,11,37,38 reinforced the choice of cis-4f as our rst hit.…”

Synthetic Approaches to Novel Human Carbonic Anhydrase Isoform Inhibitors Based on Pyrrol-2-one Moiety

“…Aiming to produce new derivatives in light of all of the above, our current work was a continuation of our earlier investigation into N -heterocycle systems − and as part of our interest in the field of physiologically active chemicals, − with a focus on carbonic anhydrase inhibitors. ,,,− The synthesis, structure, and evaluation of several novel dihydro-pyrrol-2-one derivatives as inhibitors of tumor-associated human CA are thus reported here.…”