Abstract
Colchicine, a pseudoalkaloid isolated from Colchicum autumnale, has been identified as a potent anticancer agent because of its strong antimitotic activity. It was shown that colchicine modifications by regioselective demethylation affected its biological properties. For demethylated colchicine analogs, 10-demethylcolchicine (colchiceine, 1) and 1-demethylthiocolchicine (3), a series of 12 colchicine derivatives including 5 novel esters (2b–c and 4b–d) and 4 carbonates (2e–f and 4e–f) were synthesized. The antiproliferative activity assay, together with in silico evaluation of physicochemical properties, confirmed attractive biological profiles for all obtained compounds. The substitutions of H-donor and H-acceptor sites at C1 in thiocolchicine position provide an efficient control of the hydration affinity and solubility, as demonstrated for anhydrate 3, hemihydrate 4e and monohydrate 4a.
Highlights
Colchicine (Figure 1) is a pseudoalkaloid produced by Colchicum autumnale [1]
We evaluated the antiproliferative activity of these derivatives using three human cancer cell lines, human lung adenocarcinoma (A549), human breast adenocarcinoma (MCF-7) and human colon adenocarcinoma cell line (LoVo), and one normal murine embryonic fibroblast cell line (BALB/3T3)
A series of colchicine esters and carbonates substituted at C1 and C10 positions in colchicine were synthesized by performing regioselective demethylation reactions of C1 and C10 methoxy groups, respectively
Summary
Colchicine (Figure 1) is a pseudoalkaloid produced by Colchicum autumnale [1]. Its beneficial applications have been known for centuries, as colchicine was used by ancient Greeks and Egyptians to treat swelling and inflammation [2]. The most interesting property of colchicine is its high affinity for binding to the tubulin in cancer cells, leading to the inhibition of microtubule polymerization and mitosis arrest [6,7,8]. These unique properties have attracted great interest to colchicine as an anticancer-drug candidate, its use is limited by its toxicity towards normal cells [9,10,11]. Tubulin interacts with trimethoxyphenyl ring A and tropolone ring C, making the methoxy groups at C1, C2 and C10, as well as the C9-keto group, crucial for colchicine’s antimitotic activity [25,26,27]
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