Synthesis and evaluation of novel heterocyclic compounds as anticancer agents

Mal ullah, AARA 2020, Synthesis and evaluation of novel heterocyclic compounds as anticancer agents , PhD thesis, University of Salford.

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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 %).

Item Type: Thesis (PhD)
Contributors: Hadfield, JA (Supervisor)
Schools: Schools > School of Environment and Life Sciences
Depositing User: AMJED ABDUL RAZAQ AHMED Mal ullah
Date Deposited: 07 Oct 2020 10:09
Last Modified: 30 Sep 2022 02:30

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