Abstract
Colchicine belongs to a large group of microtubule polymerization inhibitors. Although the anti-cancer activity of colchicine and its derivatives has been established, none of them has found commercial application in cancer treatment due to side effects. Therefore, we designed and synthesized a series of six triple-modified 4-chlorothiocolchicine analogues with amide moieties and one urea derivative. These novel derivatives were tested against several different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and primary acute lymphoblastic leukemia (ALL) cells and they showed activity in the nanomolar range. The obtained IC50 values for novel derivatives were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies of colchicine and selected analogues were undertaken to indicate that they induced apoptotic cell death in ALL-5 cells. We also performed in silico studies to predict binding modes of the 4-chlorothiocolchicine derivatives to different β tubulin isotypes. The results indicate that select triple-modified 4-chlorothiocolchicine derivatives represent highly promising novel cancer chemotherapeutics.
Highlights
Colchicine (1) is a plant alkaloid isolated from Colchicum autumnale [1]
Compounds 5–11 were synthesized in one pot reaction of compound 4 with respective acyl (5–10) or carbamoyl (11) chloride in the presence of triethylamine and 4-dimethylaminopyridine (DMAP)
Overall levels of mitotically arrested cells were low, with a maximum level of about 20%. This observation is in good agreement with our previous work, where we showed that other microtubule destabilizing agents such as vincristine and eribulin failed to cause mitotic arrest in acute lymphoblastic leukemia (ALL)-5 cells, and tend instead to induce death directly in G1 phase [40]
Summary
Colchicine (1) is a plant alkaloid isolated from Colchicum autumnale [1]. It is used for the treatment of acute gout, familial Mediterranean fever, Behçet's disease and pericarditis and other diseases [2,3,4,5,6,7,8,9,10,11,12]. In 2011, Hiromitsu Takayama’s research group published results of their studies on C-4 halogen substituted colchicine derivatives, including 4-chlorocolchicine [26]. A year later they published extended results of 4-chlorocolchicine derivatives bearing an amide moiety in the C-7 position [27]. Kerekes et al reported colchicine derivatives with diversified amide moieties in the C-7 position and a thiomethyl group in the C-10 position [36]. Encouraged by the previously reported results, we decided to extend the library of these potent and selective molecules by synthesizing a series of novel triple-modified amide and urea derivatives of 4-chlorothiocolchicine. The results show that several of the 4chlorocolchicine derivatives have properties superior to the parent compound, and as such represent important new leads and warrant further investigation as novel cancer drugs. Reagents and conditions: (a) NCS, acetonitrile, RT (b) MeOH/H2O, CH3SNa, RT; (c) 2 M HCl, 90 °C, 72 h; (d) Et3N, DMAP, respective acyl/carbamoyl chloride, THF, 0 °C → RT
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
