Structure-guided optimization of 4,6-substituted-1,3,5-triazin-2(1H)-ones as catalytic inhibitors of human DNA topoisomerase IIα

• Published in: European journal of medicinal chemistry 2019-08, Vol.175, p.330-348
• Main Authors: Bergant, Kaja, Janežič, Matej, Valjavec, Katja, Sosič, Izidor, Pajk, Stane, Štampar, Martina, Žegura, Bojana, Gobec, Stanislav, Filipič, Metka, Perdih, Andrej
• Format: Article
• Language: English
• Subjects: Anticancer agents; Catalytic inhibitors; Computer-aided drug design; Human DNA topoisomerase IIα; In vitro studies
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.04.055

Human DNA topoisomerases represent one of the key targets of modern chemotherapy. An emerging group of catalytic inhibitors of human DNA topoisomerase IIα comprises a new paradigm directed to circumvent the known limitations of topoisomerase II poisons such as cardiotoxicity and induction of secondary tumors. In our previous studies, 4,6-substituted-1,3,5-triazin-2(1H)-ones were discovered as catalytic inhibitors of topo IIα. Here, we report the results of our efforts to optimize several properties of the initial chemical series that did not exhibit cytotoxicity on cancer cell lines. Using an optimized synthetic route, a focused chemical library was designed aimed at further functionalizing substituents at the position 4 of the 1,3,5-triazin-2(1H)-one scaffold to enable additional interactions with the topo IIα ATP binding site. After virtual screening, selected 36 analogues were synthesized and experimentally evaluated for human topo IIα inhibition. The optimized series displayed improved inhibition of topo IIα over the initial series and the catalytic mode of inhibition was confirmed for the selected active compounds. The optimized series also showed cytotoxicity against HepG2 and MCF-7 cell lines and did not induce double-strand breaks, thus displaying a mechanism of action that differs from the topo II poisons on the cellular level. The new series represents a new step in the development of the 4,6-substituted-1,3,5-triazin-2(1H)-one class towards novel efficient anticancer therapies utilizing the catalytic topo IIα inhibition paradigm. [Display omitted] •Structure-guided optimization of 4,6-substituted-1,3,5-triazin-2(1H)-ones.•Superior human topo IIα inhibition of the synthesized compounds over the initial series.•Confirmed catalytic mode of inhibition of human DNA topoisomerase IIα.•Cytotoxicity against HepG2 and MCF-7 cancer cell lines.•No induction of double-strand breaks (DSB) in HepG2 cell line.