Synthesis, Antiproliferative Activity and Molecular Docking Studies of Novel Doubly Modified Colchicine Amides and Sulfonamides as Anticancer Agents

Abstract

Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides and sulfonamides) and at C10 (methylamino group) positions and characterized by spectroscopic methods. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX and BALB/3T3 cell lines. Additionally, the activity of the studied compounds was investigated using computational methods involving molecular docking of the colchicine derivatives to β-tubulin. The majority of the obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin or cisplatin against tested cancer cell lines. Furthermore, molecular modeling studies of the obtained compounds revealed their possible binding modes into the colchicine binding site of tubulin.

New Series of Double-Modified Colchicine Derivatives: Synthesis, Cytotoxic Effect and Molecular Docking

“…440 times more potent than unmodified colchicine 1 (IC 50 = 702.2 nM). Comparison of the results for C7-amine double-modified analogues and those of previously published studies of C7-amide double-modified analogues [20] showed that in both cases some of the most cytotoxic compounds were derivatives containing a 2-chlorobenzyl ring at position C7. These results are noteworthy and suggest that extended and more detailed research is necessary to determine the meaning and role of the above mentioned substituent.…”

“…Compound 3 was readily available from 1 by treatment with methylamine and followed by hydrolysis with 2M HCl [20,31]. N-deacetyl-10-methylamino-10-demethoxycolchicine 3 became the starting material for the synthesis of new derivatives (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

“…The tested compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) were evaluated for their in vitro antiproliferative effect on four human cancer cell lines and one normal murine embryonic fibroblast cell line according to the previously published procedure [20]. Detailed information concerning antiproliferation assay can be found in Supplementary Materials.…”

“…In our study, computational methodology (according to the previously published procedure [20]) has been employed to precisely explore the molecular basis for the binding of the fourteen novel colchicines to β-tubulin. The β-tubulin monomer together with the highly homologous β-tubulin monomer form a stable dimer, which is the building block of microtubules in the cytoskeleton structure of every eukaryotic cell.…”

“…Molecular docking studies was performed according to the previously published procedure [20] and detailed information can be found in Supplementary Materials.…”