title: 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.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA. mmullo2@uic.edu.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Mullowney
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA. eohain2@uic.edu.
authors.forename: Eoghainín
authors.initials: E
authors.lastname: Ó hAinmhire
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA. ashaikh5@gmail.com.
authors.forename: Anam
authors.initials: A
authors.lastname: Shaikh
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA. xmchuic12@gmail.com.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA. urszula.tanouye@gmail.com.
authors.forename: Urszula
authors.initials: U
authors.lastname: Tanouye
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA. bds@uic.edu.
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Santarsiero
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA. joannab@uic.edu.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Burdette
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA. btmurphy@uic.edu.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Murphy
mesh_terms: D000873:Anthracenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003460:Crystallization; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011809:Quinones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D064210:Secondary Metabolism; D013302:Streptomyces / Q000378:metabolism*; D014961:X-Ray Diffraction
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D011809:Quinones; D011065:Poly(ADP-ribose) Polymerases