Mullowney Michael W, Ó hAinmhire Eoghainín, Shaikh Anam, Wei Xiaomei, Tanouye Urszula, Santarsiero Bernard D, Burdette Joanna E, Murphy Brian T
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA.
Mar Drugs. 2014 Jun 11;12(6):3574-86. doi: 10.3390/md12063574.
As part of our program to identify novel secondary metabolites that target drug-resistant ovarian cancers, a screening of our aquatic-derived actinomycete fraction library against a cisplatin-resistant ovarian cancer cell line (OVCAR5) led to the isolation of novel diaza-anthracene antibiotic diazaquinomycin E (DAQE; 1), the isomeric mixture of diazaquinomycin F (DAQF; 2) and diazaquinomycin G (DAQG; 3), and known analog diazaquinomycin A (DAQA; 4). The structures of DAQF and DAQG were solved through deconvolution of X-Ray diffraction data of their corresponding co-crystal. DAQE and DAQA exhibited moderate LC50 values against OVCAR5 of 9.0 and 8.8 μM, respectively. At lethal concentrations of DAQA, evidence of DNA damage was observed via induction of apoptosis through cleaved-PARP. Herein, we will discuss the isolation, structure elucidation, and biological activity of these secondary metabolites.
作为我们鉴定针对耐药性卵巢癌的新型次生代谢产物计划的一部分，对我们从水生来源放线菌馏分库中筛选针对顺铂耐药性卵巢癌细胞系（OVCAR5）的研究，导致分离出新型二氮杂蒽抗生素二氮喹霉素E（DAQE；1）、二氮喹霉素F（DAQF；2）和二氮喹霉素G（DAQG；3）的异构体混合物，以及已知类似物二氮喹霉素A（DAQA；4）。通过对其相应共晶体的X射线衍射数据进行反卷积解析，确定了DAQF和DAQG的结构。DAQE和DAQA对OVCAR5的半数致死浓度（LC50）分别为9.0 μM和8.8 μM，表现出中等活性。在DAQA的致死浓度下，通过裂解PARP诱导凋亡观察到DNA损伤的证据。在此，我们将讨论这些次生代谢产物的分离、结构解析和生物活性。
