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.

Diaza-anthracene Antibiotics from a Freshwater-Derived Actinomycete with Selective Antibacterial Activity toward Mycobacterium tuberculosis

“…Fortunately, in a previous study, we isolated and identified four analogues of the diazaquinomycin antibiotic class from a marine-derived Streptomyces sp. 17 DAQs F and G were a coeluting isomeric mixture, but DAQA ( 3 ) and DAQE were purified and screened in the MABA, exhibiting MICs of 0.1 and 0.04 μ g/mL, respectively. From this strain, compound 3 was produced in relatively large amounts; thus, all further biological experiments were carried out using this molecule.…”

Total synthesis of diazaquinomycins H and J using double Knorr cyclization in the presence of triisopropylsilane

“…Diazaquinomycins (DAQs) are secondary metabolites produced by terrestrial and aquatic Actinobacteria, predominantly from the genus Streptomyces sp. [1][2][3][4][5] Spanning the last three and a half decades, nine DAQs have been reported, however, diazaquinomycins D, F, and G were not obtained in pure form (Fig. 1).…”

“…1). [1][2][3][4][5] Specically, diazaquinomycin D was a trace component in a sample of diazaquinomycin C that was produced by Streptomyces sp. GW48/1497 when cultivated in soybean our and mannitol.…”

“…3 The isomeric diazaquinomycins F and G were isolated as an inseparable mixture; 2 their structures were established using a combination of NMR and UV spectroscopy, HRMS, and X-ray crystallography. 2 Diazaquinomycins H (1) and J (2), bearing a long lipophilic side chain with a unique terminal isopropyl functionality, are the latest additions to this family and were isolated by Mullowney et al from fresh water-derived Actinobacteria in Lake Michigan. 1 Notably, diazaquinomycins H and J along with diazaquinomycin A showed excellent in vitro antibacterial activity against Mycobacterium tuberculosis (M. tuberculosis) with minimum inhibitory concentration (MIC) values of 0.04, 0.07, and 0.10 mg mL À1 , respectively.…”

Recent developments in natural product-based drug discovery for tuberculosis

“…However, it was only recently that Mullowney et al discovered the potent antimycobacterial activity of some DAQs, in the context of the isolation of the new DAQs E-G from Streptomyces sp. [57] and H and J from Micromonospora sp. [58].…”