Department of Organic Chemistry, University of Madras , Guindy Campus, Chennai 600 025, India.
Department of Biochemistry, University of Madras , Guindy Campus, Chennai 600 025, India.
J Med Chem. 2018 Feb 8;61(3):1285-1315. doi: 10.1021/acs.jmedchem.7b01797. Epub 2018 Jan 22.
A series of calothrixin B (2) analogues bearing substituents at the 'E' ring and their corresponding deoxygenated quinocarbazoles lacking quinone unit were synthesized. The cytotoxicities of calothrixins 1, 2, and 15b-p and quinocarbazole analogues were investigated against nine cancer cell lines. The quinocarbazoles 21a and 25a inhibited the catalytic activity of human topoisomerase II. The plasmid DNA cleavage abilities of calothrixins 1, 2, and 15b-p identified compound 15h causing DNA cleavage comparable to that of calothrixin A (1). Calothrixin A (1), 3-fluorocalothrixin 15h and 4-fluoroquinocarbazole 21b induced extensive DNA damage followed by apoptotic cell death. Spectral and plasmid unwinding studies demonstrated an intercalative mode of binding for quinocarbazoles. We identified two promising drug candidates, the 3-fluorocalothrixin B 15h with low toxicity in animal model and its deoxygenated derivative 4-fluoroquinocarbazole 21b as having potent cytotoxicity against NCI-H460 cell line with a GI of 1 nM.
一系列在“E”环带有取代基的 calothrixin B（2）类似物及其相应的去氧醌型喹喔啉类似物被合成。对 calothrixins 1、2 和 15b-p 以及喹喔啉类似物进行了针对九种癌细胞系的细胞毒性研究。喹喔啉 21a 和 25a 抑制了人拓扑异构酶 II 的催化活性。calothrixins 1、2 和 15b-p 的质粒 DNA 切割能力鉴定出化合物 15h 引起的 DNA 切割与 calothrixin A（1）相当。Calothrixin A（1）、3-氟 calothrixin 15h 和 4-氟喹喔啉 21b 诱导广泛的 DNA 损伤，随后发生凋亡性细胞死亡。光谱和质粒解旋研究表明，喹喔啉类化合物具有嵌入结合模式。我们确定了两种有前途的药物候选物，具有低毒性的 3-氟 calothrixin B 15h 和其去氧 4-氟喹喔啉 21b，对 NCI-H460 细胞系具有强大的细胞毒性，GI 为 1 nM。
