Design, synthesis and biological activity of novel molecules designed to target PARP and DNA

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• 作者：Elliot Goodfellow^a ; Zhor Senhaji Mouhri^a ; Christopher Williams^b ; Bertrand J. Jean-Claude^a ; ^{bertrandj.jean-claude@mcgill.ca}
• 关键词：PARP inhibitors ; BRCA mutation ; Synthetic lethality ; DNA damage ; Bis-targeting
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：688-694
• 全文大小：1754 K
• 卷排序：27

文摘

In order to enhance the cytotoxic potential of poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1 or 2 deficient tumours, we designed a series of molecules containing a 1,2,3-triazene moiety tethered to a PARP targeting scaffold. A cell-based selectivity assay involving a BRCA2-deficient Chinese hamster cell line and its corresponding BRCA2 wild type transfectant, was used to predict the PARP targeting potential of the latter agents. The results showed that adding a DNA damaging function to the PARP inhibitors decreased but did not abrogate the selective targeting of the BRCA2-deficient cells. The DNA damaging moiety augmented the potency in BRCA2 deficient cells by 2–20 fold. The most selective dual PARP–DNA targeting agent 14b was found to possess dual DNA and PARP targeting properties.