Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives.

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Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives.

Eur J Med Chem. 2017 Oct 19;:

Authors: Nadysev GY, Tikhomirov AS, Lin MH, Yang YT, Dezhenkova LG, Chen HY, Kaluzhny DN, Schols D, Shtil AA, Shchekotikhin AE, Chueh PJ

Abstract
A series of 4-aminomethyl derivatives of heliomycin 1 was prepared using the Mannich reaction. The modification significantly improved aqueous solubility of the initially poorly soluble antibiotic. Testing the antiproliferative efficacy revealed a potent activity of heliomycin as well as its new derivatives on a panel of mammalian tumor cells including drug resistant variants. In contrast to 1 the new derivatives 7a, 7l, 7p generated a high level of ROS associated with induction of apoptosis in T24 bladder cancer cells. Introduction of 4-aminomethyl moiety increased the affinity to DNA and the ability to inhibit topoisomerase 1 making 7p the most promising candidate for further preclinical evaluation. Thus, aminomethylation is the first-in-class successful transformation of the antibiotic 1 resulting in an improved water solubility of derivatives and promising properties in search of novel anticancer drug candidates.

PMID: 29137865 [PubMed - as supplied by publisher]

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