Synthesis and Antiproliferative Screening Of Novel Analogs of Regioselectively Demethylated Colchicine and Thiocolchicine

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.

A New Insight into Toxicity of Colchicine Analogues by Molecular Docking Analysis Based on Intestinal Tight Junction Protein ZO-1

“…More to the point, there was no significant difference in the BE values among these metabolites, although they had different interaction forces and the hydrogen bonding sites for complexing. These results provided additional evidence for the structure-toxicity relationship of COL analogues from a new viewpoint and were in good agreement with those cell/animal-based experimental observations previously reported [12,32]. Further, considering the fact that COL in vivo is apt to form more readily excreted metabolites, the findings from the present study thus clearly demonstrated that metabolic transformation through phase I demethylation and phase II conjugation with hydrophilic moieties would lead to in vivo detoxification for COL.…”

“…These demethylated compounds are prone to further phase II conjugation with hydrophilic moieties (i.e., glucuronate, sulfate, and glutathione) to form more readily excreted metabolites [ 30 , 31 ]. A variety of studies have also demonstrated the great changes in bioactivities of COL caused by metabolic transformation [ 32 ]. For example, COL can induce a sharp increase in the level of serum transaminases such as AST and ALT, on which the demethylated metabolites 2/3/10-DMC under the same conditions have little influence, suggesting reduced liver toxicity of COL along with metabolism [ 12 ].…”

Colchicine Alkaloids and Synthetic Analogues: Current Progress and Perspectives

“…Replacement of the C-1 methoxy group of colchicine by other alkyloxy or acyloxy groups − did not lead to significant changes in the cytotoxicity of the compounds; however, bulky substituents led to reduced activity (Scheme ). The same held true for a C-1-modified thiocolchicine …”

Lead optimization of novel quinolone chalcone compounds by a structure–activity relationship (SAR) study to increase efficacy and metabolic stability

“…Secondly, the presence of a methoxy group on the quinolone ring also adds to the efficacy of CTRs. It is known that methoxy groups are present in colchicine, and are necessary for its tubulin binding activity 31 and thus its anti-proliferative activity 32 . Our finding is consistent with this previous finding.…”