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

Ryan Nichol, Abedawn Khalaf, Kartheek Sooda, Omar Hussain, Hollie Griffiths, Roger Phillips, Farideh Javid, Colin Suckling, Simon J. Allison, Fraser Scott

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 Strathclyde Minor Groove Binders (S-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 S-MGBs with activities comparable to cis-platin and carboplatin, but with better in vitro selectivity indices, particularly S-MGB-4, S-MGB-74 and S-MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our S-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, S-MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our S-MGBs are unlikely to act through an alkylating or DNA damage response mechanism.

Original languageEnglish
Pages (from-to)1620-1634
Number of pages15
JournalMedChemComm
Volume10
Issue number9
Early online date18 Jul 2019
DOIs
Publication statusPublished - 1 Sep 2019

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    Nichol, R., Khalaf, A., Sooda, K., Hussain, O., Griffiths, H., Phillips, R., ... Scott, F. (2019). Selective in vitro anti-cancer activity of non-alkylating minor groove binders. MedChemComm, 10(9), 1620-1634. https://doi.org/10.1039/C9MD00268E