Synthesis and evaluation of novel heterocyclic compounds as anticancer agents

Mal ullah, AARA

Abstract

There is a clear need for anti-cancer therapies that have effective cytotoxic efficiency and
marginal toxicity, preferably zero. For this goal, researchers have been persevering to
develop new drugs from natural resources. Among them are agents that target tubulin,
which is a protein found in all eukaryotic cells. This protein is an essential component for
mitosis and has several different binding sites at which a variety of chemically different
agents interact. These binding sites include the colchicine, vinca alkaloids, rhizoxin
/maytansine and tubulin sulfhydryl binding sites. Combretastatin A-4 is one of the most
potent natural products targeting tubulin and prevents microtubule polymerisation that
leads to mitosis arrest and apoptosis in endothelial cells. Moreover, it can cause selective
vascular shutdown for the tumour cell and results in haemorrhagic necrosis for the solid
tumour. However, cis-combretastatin is more active than the trans isomer. Toxicity to
normal cells has limited its use as an effective chemotherapy. Another problem with this
isomer is the in vivo instability, by which the unstable cis isomer converts to the more
stable inactive trans-isomer.
To overcome this problem, many combretastatin analogues have been synthesized and
evaluated in terms of antimitotic and cytotoxic activity as well as toxicity. 6-(4-Methoxy-
3-nitrophenyl)-5-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3(2H)-one, and series of : 2,3-
diaryl-3H-imidazo[4,5-b]pyridine, and N-((2-arylamino)pyridine)benzenesulphonamide
derivatives, which related to E7010, have been synthesised as possible active analogues
of combretastatin A-4.
These heterocyclic analogues have been characterized and examined for their ability to
suppress the growth of A549, U-2 OS, BEAS-2B, Saos-2, Hep-G2, and A204 mammalian
cell lines by MTT assay, and flowcytometry. 3-Hydroxy-4-methoxy-N-(2-((3,4,5-
trimethoxybenzyl)amino)pyridin-3-yl)benzenesulfonamide, was the most potent
compound evaluated with an IC50 of 1.15µM in the Carcinoma A549 cell line. It is also
caused cells to hold up in the G2/M phase of the cell cycle (37.34 %).

Citation

Mal ullah, A. Synthesis and evaluation of novel heterocyclic compounds as anticancer agents. (Thesis). University of Salford

• Thesis Type: Thesis
• Deposit Date: Oct 7, 2020
• Publicly Available Date: Oct 7, 2020
• Award Date: Sep 30, 2020