Abstract
An extract prepared from the culture of a marine-derived actinomycete Streptomyces sp. ZZ338 was found to have significant antimicrobial and antiproliferative activities. A chemical investigation of this active extract resulted in the isolation of three known bioactive actinomycins (1–3) and two new metabolites (4 and 5). The structures of the isolated compounds were identified as actinomycins D (1), V (2), X0β (3), 2-acetylamino-3-hydroxyl-4-methyl-benzoic acid methyl ester (4), and N-1S-(4-methylaminophenylmethyl)-2-oxo-propyl acetamide (5) based on their nuclear magnetic resonance (NMR) and high resolution electrospray ionization mass spectroscopy (HRESIMS) data as well as their optical rotation. This class of new compound 5 had never before been found from a natural resource. Three known actinomycins showed activities in inhibiting the proliferation of glioma cells and the growth of methicillin-resistant Staphylococcus aureus, Escherichia coli, and Candida albicans and are responsible for the activity of the crude extract. Actinomycin D (1) was also found to downregulate several glioma metabolic enzymes of glycolysis, glutaminolysis, and lipogenesis, suggesting that targeting multiple tumor metabolic regulators might be a new anti-glioma mechanism of actinomycin D. This is the first report of such a possible mechanism for the class of actinomycins.
Highlights
Gliomas are the most aggressive and frequently diagnosed human brain tumors
While chemotherapy has played an important role in the treatment and prevention of cancer, very few drugs have been approved for treating gliomas including temozolomide (TMZ), carmustine, lomustine, and bevacizumab [2]
Several anti-cancer metabolites from marine sponges that have progressed to preclinical or clinical trial phases, such as discodermolide, halichondrin B, bryostatin1, and phorboxazole A, may be products derived from their microbiotic consortia [5,6,7]
Summary
Gliomas are the most aggressive and frequently diagnosed human brain tumors. Despite advances in therapies including chemotherapy, radiotherapy, and surgical resection, the prognosis is still very poor [1]. While chemotherapy has played an important role in the treatment and prevention of cancer, very few drugs have been approved for treating gliomas including temozolomide (TMZ), carmustine, lomustine, and bevacizumab [2]. There is an urgent need to discover lead compounds for the development of novel anti-glioma drugs. Many anti-cancer bioactive compounds, originally isolated from marine invertebrates are produced by marine microorganisms [3,4]. Several anti-cancer metabolites from marine sponges that have progressed to preclinical or clinical trial phases, such as discodermolide, halichondrin B, bryostatin, and phorboxazole A, may be products derived from their microbiotic consortia [5,6,7]. Bioactive natural products produced by marine microorganisms are promising sources for the discovery and development of novel anti-glioma drugs or drug leads [7,8,9]
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