Design, synthesis, and biological evaluation of biotinylated colchicine derivatives as potential antitumor agents

Abstract

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovering new anti-tumour drugs to improve tumour targeting effects and reduce off-target toxicities. Colchicine is one of the most prominent and historically microtubule-targeting drugs, but its clinical applications are hindered by notorious adverse effects. In this study, we presented a novel tumour-specific conjugate 9 that consists of deacetylcolchicine (Deac), biotin, and a cleavable disulphide linker. 9 was found to exhibit potent anti-tumour activity and exerted higher selectivity between tumour and nontarget cells than Deac. The targeting moiety biotin might enhance the transport capability and selectivity of 9 to tumour cells via biotin receptor-mediated endocytosis. The tubulin polymerisation activity of 9 (with DTT) was close to the parent drug Deac. These preliminary results suggested that 9 is a high potency and reduced toxicity antitumor agent and worthy of further investigation.

Design, synthesis and biological evaluation of a novel colchicine-magnolol hybrid for inhibiting the growth of Lewis lung carcinoma in Vitro and in Vivo

“…Colchicine 1) is a bioactive alkaloid originally isolated from Colchicum autumnale and has long been used as a treatment for gout ( Deng et al, 2021 ). Besides, there is extensive evidence that colchicine has displayed excellent antiproliferative potential in a variety of cancer cell lines against colon, breast, skin melanoma, liver and pancreas ( Malik et al, 2022 ; Song et al, 2022 ; Wang et al, 2022 ), and thereby entered into different stages of clinical trials as an anti-cancer agent. Mechanistic studies have revealed that colchicine arrests cell division and kills tumor cells by favorably binding to the colchicine binding site of tubulin and interfering with microtubule formation ( Dubey et al, 2017 ).…”

Design, synthesis and biological evaluation of 9-aryl-5H-pyrido[4,3-b]indole derivatives as potential tubulin polymerization inhibitors

“…Microtubules, crucial elements of the cytoskeleton, are highly dynamic frameworks formed by α - and β -tubulin and play a part in a range of physiological processes including cell mitosis, shape maintenance, intracellular material transport, and signal transmission ( Akhmanova and Steinmetz, 2015 ; Wang et al, 2022 ). Disruption of the dynamic balance of tubulin will interfere with the normal function of microtubules, lead to mitotic catastrophe and ultimately induce apoptosis ( Liu et al, 2021b ).…”