Syntheses of anticancer agents that target DNA : steroids, nucleosides, and platinums

Date

2017-01-06

Authors

Cheun, Young Kun

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Abstract

Cephalostatins from Cephalodiscus gilchristi and ritterazines from Ritterella tokioka inhibit cell growth in nanomolar concentrations by inducing unknown apoptosis pathway. Their NCI-60 growth inhibition patterns are distinctive from most of anticancer drugs. Despite their potentials as promising anticancer drugs, further preclinical/clinical studies have been halted due to the supply challenges. The Lee group has been interested in synthesizing simple and effective analogs of cephalostatin and ritterazine. New synthesis route to 17-hydroxylation of ritterazine G subunit has been discovered, and the synthesis of 14,15-dehydro-ritterazine Y from hecogenin has been completed. Histone methyltransferases (HMTs) methylate specific lysines and arginines of histones, leading to modifications of gene expression patterns. HMTs are associated with cancer, and they require S-Adenosyl methionine (SAM) as their methyl donor. The Lee group intended to design a “SAM analog–histone fragment” as a probe for studying HMTs. Synthesis of an acryloyl SAM analog has been carried out. N7 of guanine is an electron-rich atom that reacts with various endogenous and exogenous electrophiles. The resulting N7 guanine adduct facilitates the cleavage of the glycosidic bond of deoxyguanosine, making the x-ray study of those lesions difficult. The Lee group has been interested in studying how various DNA repair polymerases process various N7 lesions. We attempted to synthesize oligonucleotide that contain various N7-deaza guanine adducts. Cisplatin is a widely used anticancer small molecule that causes various intrastrand crosslinks and interstrand crosslinks (ICL) of DNA. The most common 1,2-GpG intrastrand crosslink causes a noticeable distortion of the helix, which is recognized by nucleotide excision repair (NER) proteins. Since elevated NER level is observed in cisplatin-resistant cancer cells, a cisplatin-like molecule that does not distort the helix could be useful for treating cisplatin resistance. The Lee group’s compound, carbazoleplatin, is a platinum-intercalator conjugate that causes little distortion of the platinated helix and is less efficiently processed by NER proteins. In vitro IC₅₀ were 5 – 8 times more cytotoxic than those of cisplatin against PANC-1 (pancreas) and MDA-MB-231 (breast).

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