Centre for Synthesis and Chemical Biology, Department of Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.
Dalton Trans. 2019 Jun 28;48(24):8578-8593. doi: 10.1039/c9dt00250b. Epub 2019 Apr 4.
Immunocompromised cancer patients are often at high risk of developing infections. Standard infection control measures are required to prevent the onset of infection but, under some circumstances, antimicrobial prophylaxis is necessary. We have developed a family of innovative metallo-antibiotics of general formula [Cu(N,N)(CipA)Cl] where N,N represents a phenanthrene ligand and CipA stands for a derivative of the clinically used fluoroquinolone antibiotic ciprofloxacin. The X-ray crystal structure of one member from this family, [Cu(phen)(CipA)Cl] (where phen is 1,10-phenanthroline), is also reported. These complexes combine into one drug entity a Cu-N,N-framework with DNA binding and DNA oxidant properties and an antibiotic derivative with known anti-proliferative and anti-microbial activities. The complexes were all found to exhibit excellent DNA recognition with binding affinity of lead agents in the order of ∼10 M(bp). Biophysical studies involving calf thymus DNA indicate the complexes intercalate or semi-intercalate DNA via the minor groove. All complexes exhibited excellent nuclease activity with DNA strand scission being mediated predominantly via superoxide and hydroxyl radicals. The complexes were found to have promising anti-proliferative effects against a human breast adenocarcinoma cell line (MCF-7) and a human prostate carcinoma cell line (DU145) with low micromolar and, in some cases, nanomolar cytotoxicities observed. Selective targeting of Gram positive bacteria was also identified by this complex class with one lead compound having an order of magnitude greater potency against Methicillin-resistant S. aureus (MRSA) as compared to the CipA ligand. Importantly, from a clinical stand point, these complexes were also found to be well tolerated in an in vivo Galleria mellonella larvae model, which has both functional and structural similarities to that of the innate immune system of mammals.
免疫功能低下的癌症患者通常面临较高的感染风险。需要采取标准的感染控制措施来预防感染的发生，但在某些情况下，需要进行抗菌预防。我们开发了一系列创新的金属抗生素，通式为[Cu（N，N）（CipA）Cl]，其中 N，N 代表菲咯啉配体，CipA 代表临床上使用的氟喹诺酮类抗生素环丙沙星的衍生物。还报道了该系列中的一个成员[Cu（phen）（CipA）Cl]（其中 phen 是 1,10-菲咯啉）的 X 射线晶体结构。这些配合物将具有 DNA 结合和 DNA 氧化剂特性的 Cu-N，N 骨架与具有已知抗增殖和抗微生物活性的抗生素衍生物结合为一个药物实体。这些配合物都被发现具有出色的 DNA 识别能力，其结合亲和力约为 10 M(bp)。涉及小牛胸腺 DNA 的生物物理研究表明，这些配合物通过小沟插入或半插入 DNA。所有配合物均表现出出色的核酸酶活性，主要通过超氧自由基和羟自由基介导 DNA 链断裂。这些配合物对人乳腺癌细胞系（MCF-7）和人前列腺癌细胞系（DU145）表现出有希望的抗增殖作用，其低微摩尔甚至在某些情况下纳摩尔级的细胞毒性。通过这种配合物类别还鉴定出对革兰氏阳性菌的选择性靶向，一种先导化合物对耐甲氧西林金黄色葡萄球菌（MRSA）的活性比 CipA 配体高一个数量级。重要的是，从临床角度来看，这些配合物在体内大蜡螟幼虫模型中也被发现具有良好的耐受性，该模型在功能和结构上都与哺乳动物的固有免疫系统相似。
