Hygrocins C–G, Cytotoxic Naphthoquinone Ansamycins from gdmAI-Disrupted Streptomyces sp. LZ35

Abstract

Six hygrocins, polyketides of ansamycin class, were isolated from the gdmAI-disrupted Streptomyces sp. LZ35. The planar structure of hygrocins C-E (1-3) was determined by one-dimensional and two-dimensional NMR spectroscopy and high-resolution mass spectrometry. They are derivatives of hygrocin A but differ in the configuration at C-2 and the orientation of the C-3,4 double bond. Hygrocin F(4) and G(5) were shown to be isomers of hygrocin C (1) and B (6), respectively, due to the different alkyl oxygen participating in the macrolide ester linkage. Hygrocins C, D, and F were found to be toxic to human breast cancer MDA-MB-431 cells (IC50 = 0.5, 3.0, and 3.3 μM, respectively) and prostate cancer PC3 cells (IC50 = 1.9, 5.0, and 4.5 μM, respectively), while hygrocins B, E, and G were inactive.

Activating a Cryptic Ansamycin Biosynthetic Gene Cluster To Produce Three New Naphthalenic Octaketide Ansamycins with n-Pentyl and n-Butyl Side Chains

“…Taken together, the proposed transformation of 2 to 3 represents a new type of intramolecular cyclization, producing a spiro γ-lactam moiety similar as that in hygrocins 19 and ansalactam A. 5 The incorporation of either of two rare PKS extender units in the same position on the new structures represents another new feature of the neoansamycins.…”

“…17,18 Previously, two different classes of ansamycins, geldanamycins and hygrocins, have been isolated from strain LZ35, 19,20 which means the supply of starter unit AHBA is not responsible for the silence of the nam gene cluster. To induce the expression of the nam gene cluster, we first conducted a promoter replacement.…”

“…The stereochemistry of 3 was proposed by comparison to that of 2 and by comparison with that of hygrocins. 19,23 The formation of 3 was proposed to be derived from 2 (Scheme 1).…”

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

“…6,7 Previously, we have adapted this method to establish a library of plant-associated and marinederived actinomycetes, 8 and discovered novel ansamycins including hygrocins, 8,9 divergolides, 10,11 juanlimycins, 12 neoansamycins, 13 and ansatrienins.…”

Cuevaenes C–E: Three new triene carboxylic derivatives from Streptomyces sp. LZ35ΔgdmAI

“…This finding suggests the potential of LZ35 to produce 3-HBA-containing polyketides [4]. A gdmAI (encoding the first geldanamycin PKS module) deletion strain LZ35Δ gdmAI was constructed [3,5], as the production of geldanamycins was much higher than other constituents in this strain. This mutant could provide a relatively “clean” background to facilitate the isolation of minor constituents.…”