School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork T12 K8AF, Ireland.
Org Biomol Chem. 2020 Jan 22;18(3):557-568. doi: 10.1039/c9ob02441g.
The isoquinolinequinone (IQQ) pharmacophore is a privileged framework in known cytotoxic natural product families, caulibugulones and mansouramycins. Exploiting both families as a chemical starting point, we report on the structured development of an IQQ N-oxide anticancer framework which exhibits growth inhibition in the nM range across melanoma, ovarian and leukaemia cancer cell lines. A new lead compound (16, R6 = benzyl, R7 = H) exhibits nM GI50 values against 31/57 human tumour cell lines screened as part of the NCI60 panel and shows activity against doxorubicin resistant tumour cell lines. An electrochemical study highlights a correlation between electropositivity of the IQQ N-oxide framework and cytotoxicity. Adduct binding to sulfur based biological nucleophiles glutathione and cysteine was observed in vitro. This new framework possesses significant anticancer potential.
异喹啉醌（IQQ）药效团是已知细胞毒性天然产物家族（考利布古隆和曼苏罗霉素）中的一个重要结构。我们以这两个家族为化学起点，对 IQQ N-氧化物抗癌骨架进行了有针对性的开发，该骨架在纳摩尔范围内对黑色素瘤、卵巢癌和白血病癌细胞系表现出抑制生长作用。一种新的先导化合物（16，R6=苄基，R7=H）对 NCI60 面板筛选的 31/57 个人类肿瘤细胞系的 GI50 值达到纳摩尔级，并对多柔比星耐药肿瘤细胞系表现出活性。电化学研究突出了 IQQ N-氧化物骨架的正电性与细胞毒性之间的相关性。体外观察到该化合物与含硫生物亲核试剂谷胱甘肽和半胱氨酸的加合物结合。这个新的骨架具有显著的抗癌潜力。
