Antibacterial and Cytotoxic Actinomycins Y6-Y9 and Zp from Streptomyces sp. Strain Gö-GS12

Abstract

Four new Y-type actinomycin analogues named Y₆-Y₉ (1-4) were isolated and characterized from the scale-up fermentation of the Streptomyces sp. strain Gö-GS12, as well as actinomycin Zp (5), which was, for the first time, isolated as a natural product. Structures of the new compounds were elucidated by the cumulative analyses of NMR spectroscopy and HRMS. The 4-hydroxythreonine on the β-ring of 1 uniquely undergoes both a rearrangement by a 2-fold acyl shift and an additional ring closure with the amino group of the phenoxazinone chromophore, and the α-rings of 4 and 5 contain a rare 5-methyl proline. Compounds 2-5 showed potent antibacterial activities against Gram-positive bacteria that correlated with cytotoxicity against representative human cell lines. The combination of a β-ring rearrangement and additional ring closure in 1 rendered this actinomycin significantly less potent relative to the nonrearranged comparator actinomycin Y₅ and other actinomycins.

Figure 1

Structures of actinomycins. (A) Cartoon depiction of the general structure of all actinomycins highlighting key connectivity variations found in the β-ring. (B) Structure of the clinically approved actinomycin D, an iso-actinomycin that is isolated from several unique strains of actinomycetes. (C) Actinomycins isolated and structurally characterized from Streptomyces sp. strain Gö-GS12.

Figure 2

¹H,¹H-COSY (▬) and selected HMBC (→) correlations of actinomycins Y₆ (1), Y₇ (2) and Zp (5)