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Synthesis, antimicrobial activity and cytotoxicity of triphenylphosphonium (TPP) conjugates of 1,2,3-triazolyl nucleoside analogues
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2021-09-03 , DOI: 10.1016/j.bioorg.2021.105328
Irina Yu Strobykina 1 , Alexandra D Voloshina 1 , Olga V Andreeva 1 , Anastasiia S Sapunova 1 , Anna P Lyubina 1 , Syumbelya K Amerhanova 1 , Mayya G Belenok 1 , Liliya F Saifina 1 , Vyacheslav E Semenov 1 , Vladimir E Kataev 1
Affiliation  

Four new triphenylphosphonium (TPP) conjugates of 1,2,3-triazolyl nucleoside analogues were synthesized by coupling with 8-bromoctyl- or 10- bromdecyltriphenylphosphonium bromide and evaluated for the in vitro antibacterial activity against S. aureus, B. cereus, E. faecalis, two MRSA strains isolated from patients and resistant to fluoroquinolone antibiotic ciprofloxacin and β-lactam antibiotic amoxicillin, E. coli, antifungal activity against T. mentagrophytes C. albicans and cytotoxicity against human cancer cell lines M−HeLa, MCF-7, A549, HuTu-80, PC3, PANC-1 and normal cell line Wi-38. In these compounds a TPP cation was attached via an octyl or a decyl linker to the N 3 atom of the heterocycle moiety (thymine, 6-methyluracil, quinazoline-2,4-dione) which was bonded with 2′,3′,5′-tri- O - acetyl-greek beta-d-ribofuranose residue by the (1,2,3-triazol-4-il)methyl bridge. All synthesized compounds showed high antibacterial activity against S. aureus within the range of MIC values 1.2–4.3 greek muM, and three of them appeared to be bactericidal with respect to tis bacterium at MBC values 4.1–4.3 greek muM. Two lead compounds showed both high antibacterial activity against the MRSA strains resistant to Ciprofloxacin and Amoxicillin within the range of MIC values 1.0–4.3 greek muM and high cytotoxicity against human cancer cell lines HuTu-80 and MCF-7 within the range of IC50 values 6.4–10.2 greek muM. This is one of the few examples when phosphonium salts exhibited both antibacterial activity and cytotoxicity against human cancer cell lines. According to the results obtained the bactericidal effect of the lead compounds, unlike classical surfactants, was not caused by a violation of the integrity of the cytoplasmic membrane of bacteria and their cytotoxic activity is most likely associated both with the induction of apoptosis along the mitochondrial pathway and the arrest of the cell cycle in the G0/G1 phase.



中文翻译:

1,2,3-三唑基核苷类似物的三苯基鏻 (TPP) 缀合物的合成、抗菌活性和细胞毒性

通过与 8-溴辛基或 10-溴癸基三苯基溴化鏻偶联合成了四种新的 1,2,3-三唑基核苷类似物的三苯基鏻 (TPP) 缀合物,并评估了对金黄色葡萄球菌蜡状芽孢杆菌大肠杆菌的体外抗菌活性。粪肠球菌,从患者身上分离的两种 MRSA 菌株,对氟喹诺酮类抗生素环丙沙星和 β-内酰胺类抗生素阿莫西林、大肠杆菌白色念珠菌的抗真菌活性以及对人类癌细胞系 M-HeLa、MCF-7、A549、HuTu-80、PC3、PANC-1 和正常细胞系 Wi-38 的细胞毒性。在这些化合物中,TPP 阳离子通过辛基或癸基接头连接到与 2',3',5 键合的杂环部分(胸腺嘧啶、6-甲基尿嘧啶、喹唑啉-2,4-二酮)的 N 3 原子'-三-O-乙酰基-希腊β- d-呋喃核糖残基由(1,2,3-三唑-4-il)甲基桥组成。所有合成的化合物均对金黄色葡萄球菌显示出高抗菌活性在 MIC 值 1.2-4.3 希腊 muM 的范围内,其中三个似乎对 MBC 值 4.1-4.3 希腊 muM 的 tis 细菌具有杀菌作用。两种先导化合物在 MIC 值 1.0–4.3 希腊 muM 范围内对环丙沙星和阿莫西林耐药的 MRSA 菌株显示出高抗菌活性,并在 IC 50范围内对人类癌细胞系 HuTu-80 和 MCF-7 显示出高细胞毒性值 6.4–10.2 希腊 muM。这是鏻盐对人类癌细胞系表现出抗菌活性和细胞毒性的少数例子之一。根据获得的结果,与经典表面活性剂不同,先导化合物的杀菌作用不是由破坏细菌细胞质膜的完整性引起的,它们的细胞毒活性很可能与沿线粒体途径诱导细胞凋亡有关细胞周期在 G0/G1 期停滞。

更新日期:2021-09-07
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