Association of abnormal metabolism of choline-containing phospholipids with various cancers has resulted in the identification of enzymes involved in the phosphocholine cycle as potential therapeutic targets. Phosphatidyl-choline specific phospholipase C (PC-PLC) plays a pivotal role in this cycle and has been implicated in many signalling processes, demonstrating overexpression in various cancerous tumours, thus providing a viable target for inhibition of cancer cell growth. By virtue of virtual high throughput screening, a number of lead compounds were identified as inhibitors of the PC-PLC enzyme, including 4-amino-N-benzylanilines and pyrido[3,4-b]indoles, all of which were identified to bind to key zinc atoms at the active site. To study the PC-PLC inhibitory activity of these compounds and to verify their SAR, an extensive range of novel analogues have been synthesised, varying a number of different structural features (fig. 1). Analysis of the biological activity of the synthesised analogues showed significantly improved inhibitory activity over the only well-documented PC-PLC inhibitor, D609. These results, as well as the antiproliferative activities of the synthesised compounds will be reported, providing a comprehensive SAR of these potent compounds and their potential therapeutic applications.

Synthesis of novel, potent phosphatidyl-choline specific phospholipase C inhibitors

256th National Meeting (2018)

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