N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia.
Novosibirsk State University, Pirogova str. 1, Novosibirsk 630090, Russia.
Int J Mol Sci. 2020 Sep 28;21(19):7162. doi: 10.3390/ijms21197162.
A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure-activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors.
一系列小檗碱和四氢小檗碱磺酸盐衍生物被制备并针对酪氨酰-DNA 磷酸二酯酶 1（Tdp1）DNA 修复酶进行了测试。小檗碱衍生物在低微摩尔范围内抑制 Tdp1 酶；这是首次报道的基于小檗碱的 Tdp1 抑制剂。构效关系分析表明，在四氢小檗碱骨架的 12 位上的溴取代的重要性。此外，还表明在 9 位添加含有多氟芳族部分的磺酸盐基团可提高效力，而大多数在相同位置具有烷基片段的衍生物则没有活性。根据分子建模，12 位的溴原子与组氨酸 493 形成氢键，组氨酸 493 是关键的催化残基。在宫颈癌 HeLa 细胞系中，拓扑替康，一种临床上重要的拓扑异构酶 1 抑制剂的细胞毒性作用增加了两倍，由衍生物 11g 和 12g 引起；两者均显示出低毒性，而无拓扑替康。因此，衍生物 11g 和 12g 可进一步开发用于增敏临床相关 Topo1 抑制剂的作用。
