Idowu Temilolu, Schweizer Frank
Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada.
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3T 1R9, Canada.
Antibiotics (Basel). 2017 Nov 7;6(4):26. doi: 10.3390/antibiotics6040026.
Fluoroquinolones are synthetic antibacterial agents that stabilize the ternary complex of prokaryotic topoisomerase II enzymes (gyrase and Topo IV), leading to extensive DNA fragmentation and bacteria death. Despite the similar structural folds within the critical regions of prokaryotic and eukaryotic topoisomerases, clinically relevant fluoroquinolones display a remarkable selectivity for prokaryotic topoisomerase II, with excellent safety records in humans. Typical agents that target human topoisomerases (such as etoposide, doxorubicin and mitoxantrone) are associated with significant toxicities and secondary malignancies, whereas clinically relevant fluoroquinolones are not known to exhibit such propensities. Although many fluoroquinolones have been shown to display topoisomerase-independent antiproliferative effects against various human cancer cells, those that are significantly active against eukaryotic topoisomerase show the same DNA damaging properties as other topoisomerase poisons. Empirical models also show that fluoroquinolones mediate some unique immunomodulatory activities of suppressing pro-inflammatory cytokines and super-inducing interleukin-2. This article reviews the extended roles of fluoroquinolones and their prospects as lead for the unmet needs of "small and safe" multimodal-targeting drug scaffolds.
氟喹诺酮类是合成抗菌剂，可稳定原核拓扑异构酶II（gyrase和Topo IV）的三元复合物，导致广泛的DNA片段化和细菌死亡。尽管原核和真核拓扑异构酶的关键区域内存在相似的结构折叠，但临床相关的氟喹诺酮类对原核拓扑异构酶II表现出显著的选择性，在人类中具有出色的安全记录。靶向人类拓扑异构酶的典型药物（如依托泊苷、阿霉素和米托蒽醌）与显著的毒性和继发性恶性肿瘤有关，而临床相关的氟喹诺酮类则未显示出此类倾向。尽管许多氟喹诺酮类已被证明对各种人类癌细胞具有拓扑异构酶非依赖性的抗增殖作用，但那些对真核拓扑异构酶具有显著活性的药物与其他拓扑异构酶毒物具有相同的DNA损伤特性。经验模型还表明，氟喹诺酮类介导一些独特的免疫调节活性，可抑制促炎细胞因子并超诱导白细胞介素-2。本文综述了氟喹诺酮类的扩展作用及其作为满足“小而安全”多靶点药物支架未满足需求的先导物的前景。
