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

Julia Krzywik,Maral Aminpour,Adam Huczyński,Ewa Maj,Witold Mozga,Jack A Tuszyński,Joanna Wietrzyk

doi:10.3390/molecules25153540

Abstract

Colchicine is a well-known anticancer compound showing antimitotic effect on cells. Its high cytotoxic activity against different cancer cell lines has been demonstrated many times. In this paper we report the syntheses and spectroscopic analyses of novel colchicine derivatives obtained by structural modifications at C7 (carbon-nitrogen single bond) and C10 (methylamino group) positions. All the obtained compounds have been tested in vitro to determine their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX, and BALB/3T3 cell lines. The majority of obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin and cisplatin against the tested cancerous cell lines. Additionally, most of the presented derivatives were able to overcome the resistance of LoVo/DX cells. Additionally, their mode of binding to β-tubulin was evaluated in silico. Molecular docking studies showed that apart from the initial amides 1 and 2, compound 14, which had the best antiproliferative activity (IC50 = 0.1–1.6 nM), stood out also in terms of its predicted binding energy and probably binds best into the active site of βI-tubulin isotype.

Highlights

Tubulin is the target of some of the most widely used anticancer anti-mitotic agents, such as vinblastine or paclitaxel [1,2]
The synthetic routes to colchicine derivatives 2–17 are outlined in Scheme 1
Aldehydes used in the present paper did not require activation with acid, so the reactions were carried out without the addition of acetic acid, which eliminated the formation of unidentified by-products

Summary

Introduction

Tubulin is the target of some of the most widely used anticancer anti-mitotic agents, such as vinblastine or paclitaxel [1,2]. Colchicine 1 (see Scheme 1) is a plant-based alkaloid extracted from Colchicum autumnale and Gloriosa superba that shows antimitotic effects on a number of cancer cell lines It binds to tubulin, inhibiting its assembly and microtubule polymerization and arresting cell division at metaphase [6,7,8,9,10,11,12]. In addition to the problem with cancer cells developing drug resistance, colchicine was found to have some toxic effects, including accumulation in the gastrointestinal tract, as well as neurotoxicity [6,13,14,15,16,17,18,19] These are the two main disadvantages that limit the use of colchicine in chemotherapy

Methods

Results

Conclusion