Authors
J Reynisson4; A L Zakharenko3; O A Luzina2; V I Kaledin1; V P Nikolin1; N A Popova1; J Patel5; O D Zakharova3; A A Chepanova3; A Zafar5; E Leung5; I Leung5; N F Salakhutdinov2; O I Lavrik3;
1 Institute of Cytology and Genetics, Novosibirsk, Russian Federation; 2 N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Novosibirsk, Russian Federation; 3 Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Novosibirsk, Russian Federation; 4 School of Pharmacy, Keele University, UK; 5 University of Auckland, New Zealand
Abstract
The druggability of the tyrosyl-DNA phosphodiesterase 1 (Tdp1) enzyme was investigated in conjunction with topoisomerase 1 inhibition. A novel class of thiazole, aminothiazole and hydrazinothiazole usnic acid derivatives were synthesized and evaluated as Tdp1 inhibitors and their ability to sensitize tumors to topotecan, a topoisomerase inhibitor in clinical use. Of all the compounds tested, four hydrazinothiazole derivatives, 20c, 20d, 20h and 20i, inhibited the enzyme in the nanomolar range. The inhibitory efficiency of the compounds was verified by measuring of their affinity as well as supported by molecular modelling. The most effective Tdp1 inhibitor, 20d, was ton-toxic and increased the effect of topotecan both in vitro and in vivo in the Lewis lung carcinoma model. Furthermore, 20d showed significant increase in the antitumor and antimetastatic effect of topotecan in mice. The results presented here justify compound 20d to be considered as a drug lead for antitumor therapy.Reference: Zakharenko et al. Eur. J. Med. Chem. 161 (2019) 581-593.
PDF supporting document