Absolute Configuration and Antitumor Activity of Myxochelin A Produced by Nonomuraea pusilla TP-A0861†

Abstract

In the screening of antitumor compounds from microbial secondary metabolites, myxochelin A was isolated from a culture broth of Nonomuraea pusilla TP-A0861. The absolute configuration was determined to be S by synthesizing both enantiomers from an L-or D-lysine derivative and comparing their specific rotations. Both enantiomers of myxochelin A showed remarkable inhibitory effects on the invasion of murine colon 26-L5 carcinoma cells at non-cytotoxic concentrations. Keywords myxochelin A, invasion, antitumor, Nonomuraea IntroductionTumor invasion is the major cause of treatment failure and death in cancer patients. The process of invasion into the basement membrane is a cascade of sequential complex steps, mainly consisting of tumor cell adhesion, enzymatic degradation of extracellular matrix proteins, and migration [1]. Compounds that inhibit any of these steps are expected to be candidates of anti-metastatic and/or anti-invasive agents. Hence, the clinical efficacy of such invasive inhibitors in cancer chemotherapy are extensively exploited [2,3].In the screening for anti-invasive compounds from natural products, myxochelin A (1) was found to inhibit the in vitro tumor cell invasion. Herein, we describe the isolation, structure determination, synthesis and biological properties of 1. Results and Discussion Screening and Structure DeterminationThe screening method employed in this study is based on the experimental model of tumor cell invasion using Transwell cell culture chamber and Matrigel, the reconstituted basement membrane [4]. This bioassay enables the detection of compounds that inhibit cell adhesion, enzymatic degradation of extracellular matrix, or migration. While screening for anti-invasive compounds from our natural products library, significant activity was shown by myxochelin A (1, Fig. 1

The genus Nonomuraea: A review of a rare actinomycete taxon for novel metabolites

“…Surprisingly, both compounds showed similar level to inhibit invasion of murine colon 26‐L5 carcinoma cells. Moreover, difference in isomeric forms of such enantiomers ( R ) and ( S ) of myxochelin A has no influence on the inhibitory level against those carcinoma cells . Other non‐elucidated anticancer substances have been found in crude ethyl acetate extract of N .…”

“…More examples of anticancer or antitumor metabolites produced by this genus are myxochelin A (Fig. 1d) from N. pusilla TP-A0861 [67] and a novel antitumor brartemicin (Fig. 1e) from Nonomuraea sp.…”

Myxochelins Target Human 5-Lipoxygenase

“…15 Compound 2, which eluted after 1 from the reversed-phase HPLC column, possessed almost identical NMR spectra. A unique singlet at 3.86 ppm in the 1 H NMR spectrum together with an additional carbon signal at 56.7 ppm suggested that an aromatic hydroxy of myxochelin A is replaced by a methoxy group in 2.…”

Total (Bio)Synthesis: Strategies of Nature and of Chemists

“…This siderophore, which is produced by Stigmatella aurantiaca [122] and Nonomuraea pusilla [123], is comprised of two DHB residues ( 75 ) attached to the amino groups of lysine ( 76b ), and has also been shown to possess antitumor activity [123]. The initial stages of 65 biosynthesis parallel those of 64 , with production of DHB ( 75 ) via the EntC, EntB, and EntA homologs, MxcD, MxcF, and MxcC (Fig.…”

“…Similarly, the synthetic strategy to 65 reflects this biosynthetic approach, with the reduction of a t -Boc-protected lysine 108 to the corresponding alcohol, removal of the protecting groups to give 109 , and subsequent installation of benzylated 2,3-DHB 110 (Fig. 20) [123]. Following this, the benzyl groups were removed to afford the final compound 65 in 23% overall yield.…”