N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9, Lavrent'ev Ave., 630090 Novosibirsk, Russia.
Institute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrent'ev Ave., 630090 Novosibirsk, Russia.
Molecules. 2021 Dec 23;27(1):72. doi: 10.3390/molecules27010072.
A series of deoxycholic acid (DCA) amides containing benzyl ether groups on the steroid core were tested against the tyrosyl-DNA phosphodiesterase 1 (TDP1) and 2 (TDP2) enzymes. In addition, 1,2,4- and 1,3,4-oxadiazole derivatives were synthesized to study the linker influence between a -bromophenyl moiety and the steroid scaffold. The DCA derivatives demonstrated promising inhibitory activity against TDP1 with IC in the submicromolar range. Furthermore, the amides and the 1,3,4-oxadiazole derivatives inhibited the TDP2 enzyme but at substantially higher concentration. Tryptamide and -bromoanilide derivatives containing benzyloxy substituent at the C-3 position and non-substituted hydroxy group at C-12 on the DCA scaffold inhibited both TDP1 and TDP2 as well as enhanced the cytotoxicity of topotecan in non-toxic concentration in vitro. According to molecular modeling, ligand is anchored into the catalytic pocket of TDP1 by one hydrogen bond to the backbone of Gly458 as well as by π-π stacking between the indolyl rings of the ligand and Tyr590, resulting in excellent activity. It can therefore be concluded that these derivatives contribute to the development of specific TDP1 and TDP2 inhibitors for adjuvant therapy against cancer in combination with topoisomerase poisons.
一系列含有甾体核心上苄基醚基团的脱氧胆酸酰胺被测试对酪氨酰-DNA 磷酸二酯酶 1（TDP1）和 2（TDP2）酶的抑制活性。此外，还合成了 1,2,4-和 1,3,4-噁二唑衍生物，以研究 -溴苯基部分和甾体支架之间的连接体影响。DCA 衍生物对 TDP1 表现出有希望的亚微摩尔范围内的抑制活性。此外，酰胺和 1,3,4-噁二唑衍生物抑制 TDP2 酶，但浓度要高得多。在 DCA 支架的 C-3 位置含有苄氧基取代基和 C-12 位未取代的羟基的色氨酰胺和 -溴苯甲酰胺衍生物既抑制 TDP1 和 TDP2，又在体外非毒性浓度下增强拓扑替康的细胞毒性。根据分子建模，配体 与 Gly458 的骨架形成一个氢键，并通过配体的吲哚环与 Tyr590 之间的 π-π 堆积，锚定在 TDP1 的催化口袋中，从而具有优异的活性。因此，可以得出结论，这些衍生物有助于开发与拓扑异构酶毒物联合用于癌症辅助治疗的特异性 TDP1 和 TDP2 抑制剂。
