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  • Structure-guided optimization of 4,6-substituted-1,3,5-triazin-2(1H)-ones as catalytic inhibitors of human DNA topoisomerase ▫$II\alpha$▫
    Bergant Loboda, Kaja ...
    Human DNA topoisomerases represent one of the key targets of modern chemotherapy. An emerging group of catalytic inhibitors of human DNA topoisomerase IIslpha 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 II alpha. 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 II alpha ATP binding site. After virtual screening, selected 36 analogues were synthesized and experimentally evaluated for human topo II alpha inhibition. The optimized series displayed improved inhibition of topo IIalpha 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-7cell 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 substituted-1,3,5-triazin-2(1H)-one class towards novel efficient anticancer therapies utilizing the catalytic topo II alpha inhibition paradigm.
    Vir: European journal of medicinal chemistry. - ISSN 0223-5234 (Vol. 175, Aug. 2019, str. 330-348)
    Vrsta gradiva - članek, sestavni del
    Leto - 2019
    Jezik - angleški
    COBISS.SI-ID - 6615834

    Povezava(-e):

    https://www.sciencedirect.com/science/article/pii/S0223523419303733
    DOI

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