Abstract
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.
Highlights
Since the 1940s, natural products have proven essential as both a direct source of small molecule cancer therapies and as an inspiration for biologically active synthetic analogs of natural products; in total 131 of the 175 small molecule cancer drugs are natural products or are derived from natural products [1]
Screening of our actinomycete secondary metabolite library against the ovarian cancer cell line OVCAR5 led to the selection of strain F001 for further chemical investigation
The molecular formula was assigned as C23H28N2O4 on the basis of combined nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (MS) experiments
Summary
Since the 1940s, natural products have proven essential as both a direct source of small molecule cancer therapies and as an inspiration for biologically active synthetic analogs of natural products; in total 131 of the 175 small molecule cancer drugs are natural products or are derived from natural products [1]. Ovarian cancer, which is the fifth leading cause of cancer death and most lethal gynecological disease in US women, would greatly benefit from new therapies [2]. Our program explores the capacity of actinomycete bacteria isolated from both marine and freshwater environments to produce biologically active secondary metabolites. After several chromatographic purification steps using bioassay-guided fractionation, we isolated diazaquinomycin E (DAQE; 1), the isomeric mixture of diazaquinomycins F and G (DAQF, 2; DAQG, 3), and the known analog diazaquinomycin. Further biological evaluation was performed on the most abundant analog, DAQA, while we were unable to evaluate the biological activity of the isomeric mixture of DAQF and DAQG due to their low mass yield. Details of the elucidation and biological activities are described
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