Selective in vitro anti-cancer activity of non-alkylating minor groove binders

Nichol, Ryan and Khalaf, Abedawn and Sooda, Kartheek and Hussain, Omar and Griffiths, Hollie and Phillips, Roger and Javid, Farideh and Suckling, C. J. and Allison, Simon and Scott, Fraser (2019) Selective in vitro anti-cancer activity of non-alkylating minor groove binders. Medicinal Chemistry Communications, 10 (9). pp. 1620-1634. ISSN 2040-2511

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    Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating minor groove binders (MGBs), including 14 novel compounds, for in vitro anti-cancer activity against a human colon carcinoma cell line, a cisplatin-sensitive ovarian cancer cell line and a cisplatin-resistant ovarian cancer cell line. A human non-cancerous retinal epithelial cell line was used to measure selectivity of any response. We have identified several MGBs with activities comparable to cis-platin and carboplatin, but with better in vitro selectivity indices, particularly MGB-4, MGB-74 and MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our MGBs do not show cross resistance with cisplatin or carboplatin and that they likely have a different mechanism of action. Finally, we present an initial investigation into the mechanism of action of one compound from this class, MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our MGBs are unlikely to act through an alkylating or DNA damage response mechanism.