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
Antitumor Anthraquinones from an Endophytic Actinomycete Micromonospora lupini sp. nov. -Two novel anthraquinones, lupinacidins A (Ia) and B (Ib), are isolated from the culture broth of a new endophytic actinomycete belonging to the genus Micromonospora. Lupinacidins show significant inhibitory effects on the invasion of murine colon 26-L5 carcinoma cells without inhibiting cell growth. -(IGARASHI*, Y.; TRUJILLO, M. E.; MARTINEZ-MOLINA, E.; YANASE, S.; MIYANAGA, S.; OBATA, T.; SAKURAI, H.; SAIKI, I.; FUJITA, T.; FURUMAI, T.; Bioorg. Med.
Bioactive Microbial Metabolites. Part 30. Absolute Configuration and Antitumor Activity of Myxochelin A Produced by Nonomuraea pusilla TP-A0861. -In the screening of antitumor compounds from microbial secondary metabolites, myxochelin A (I) is isolated from the culture broth of the title actinomycete. The absolute configuration is determined to be (S). Both enantiomers show remarkable inhibitory effects on the invasion of murine colon 26-L5 carcinoma cells at non-cytotoxic concentrations. -(MIYANAGA, S.; OBATA, T.; ONAKA, H.; FUJITA, T.; SAITO, N.; SAKURAI, H.; SAIKI, I.; FURUMAI, T.; IGARASHI*, Y.; J. Antibiot. 59 (2006) 11, 698-703; Dep. Eng., Toyama Prefect. Univ., Imizu, Toyama 939, Japan; Eng.) -H. Haber
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