Ansavaricins F–I, new DNA topoisomerase inhibitors produced by Streptomyces sp. S012

Abstract

Ansamycins are a family of macrolactams characterized by an aromatic chromophore with an aliphatic chain (ansa chain) connected back to a nonadjacent position through an amide bond. In this study, four new polyketides of ansamycin class, designated as ansavaricins F-I (1-4), were obtained from the Streptomyces sp. S012 strain. All the compounds were structurally characterized as open-chain streptovaricin derivatives by using NMR and HRESIMS techniques, and showed different degrees of inhibition against human DNA topoisomerases. Ansavaricin H is a promising lead for the development of new inhibitors of human DNA topoisomerases.

Modifications, biological origin and antibacterial activity of naphthalenoid ansamycins

“…In turn, much more biological attractive were ansavaricins F-I, named as "polyketides of ansamycin class". 84 This description is, however, not precise because each of these ansavaricins F-I possesses cleavaged the ansa chain and, hence these polyketides can be only precursors or metabolites of ansamycins (called ansavaricins). Open-ansa chain ansavaricins were potent inhibitors toward human DNA topoisomerases (Topo I and Topo IIa) and one of them, i.e.…”

“…ansavaricin H exhibited selectively cytotoxicity toward HeLa and MDA-MB-453 cancer cells at IC 50 s < 50 mM. 84 It is a surprising result that for ansavaricins belonging to classical ansamycins with the ansa bridge the biological potency was lower or none, in contrast to their open-ansa chain congeners.…”

Neoansamycins from Streptomyces sp. LZ35

“…4 From these AHBA synthase gene-positive strains, we isolated dozens of ansamycins, including hygrocins, [5][6][7] divergolides, 8,9 juanlimycins, 10 ansatrienes, 11,12 and streptovaricin derivatives ansavaricins A-I. 13,14 Recently, Streptomyces sp. LZ35 was activated to produce novel naphthalenic ansamycins (neoansamycins A-C) by constitutive overexpression of a LuxR family transcriptional regulatory gene, 15 and further ten new benzenic ansamycins (5,10-seco-neoansamycins A-J) were obtained by disrupting the nam7 gene in the SR201nam1OE strain.…”

“…13 C NMR spectroscopic data for compounds 1-6 (recorded at 150 MHz, compounds 1, 2, 4, 5 in CD 3 OD and 3, 6 in DMSO-d 6 )…”