Diazaquinomycins E-G, novel diaza-anthracene analogs from a marine-derived Streptomyces sp.

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.

• Authors: Michael W Mullowney, Eoghainín Ó hAinmhire, Anam Shaikh, Xiaomei Wei, Urszula Tanouye, Bernard D Santarsiero, Joanna E Burdette, Brian T Murphy
• Journal: Marine drugs (Mar Drugs) Vol. 12 Issue 6 Pg. 3574-86 (Jun 11 2014) ISSN: 1660-3397 [Electronic] Switzerland
• PMID: 24921978 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anthracenes
• Antineoplastic Agents
• Quinones
• Poly(ADP-ribose) Polymerases

Topics

• Anthracenes (chemistry, isolation & purification, pharmacology)
• Antineoplastic Agents (chemistry, isolation & purification, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Crystallization
• DNA Damage (drug effects)
• Drug Resistance, Neoplasm
• Female
• Humans
• Lethal Dose 50
• Ovarian Neoplasms (drug therapy, pathology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Quinones (chemistry, isolation & purification, pharmacology)
• Secondary Metabolism
• Streptomyces (metabolism)
• X-Ray Diffraction