Macbecin I

Chemogenomic analysis identifies Macbecin II as a compound specific for SMAD4-negative colon cancer cells.[Pubmed:20331650]

Chem Biol Drug Des. 2010 Apr;75(4):360-8.

The tumor suppressor gene, SMAD4, is mutated in approximately 30% of colon cancers. To identify compounds with enhanced potency on cells with a SMAD4-negative context, we combined genomic and cheminformatic analyses of publicly available data relating to the colon cancer cell lines within the NCI60 panel. Two groups of cell lines were identified with either wild-type or negative SMAD4 status. A cheminformatic analysis of the NCI60 screening data was carried out, which led to the identification of 14 compounds that preferentially inhibited cell growth of the SMAD4-negative cell lines. Using cell viability assays, the effect of these compounds was validated on four colon cancer cell lines: HCT-116 and HCT-15 (SMAD4-expressing), and HT-29 and COLO-205 (SMAD4-negative). Our data identified Macbecin II, a hydroquinone ansamycin antibiotic, as having increased potency in the SMAD4-negative cells compared to SMAD4 wild-type cells. In addition, we showed that silencing of SMAD4 using siRNA in HCT-116 enhanced Macbecin II potency. Our results demonstrate that Macbecin II is specifically active in colon cancer cells having a SMAD4-negative background and thus is a potential candidate for further investigation in a drug discovery perspective.

Studies on the syntheses of benzoquinone ansamycin antibiotics. Syntheses of the C5-C15 subunits of macbecin I, geldanamycin, and herbimycin A.[Pubmed:16706538]

Org Lett. 2006 May 25;8(11):2409-12.

[reaction: see text] A general and convergent route to the C(5)-C(15) subunits of the benzoquinone ansamycin antibiotics Macbecin I, geldanamycin, and herbimycin A is described. Each subunit is prepared by the stepwise coupling of differentially functionalized aldehydes with a pentenyl dianion equivalent derived from diastereoselective pentynylation and regioselective reductive coupling.

Molecular characterization of macbecin as an Hsp90 inhibitor.[Pubmed:18357975]

J Med Chem. 2008 May 8;51(9):2853-7.

Macbecin compares favorably to geldanamycin as an Hsp90 inhibitor, being more soluble, stable, more potently inhibiting ATPase activity (IC50 = 2 microM) and binding with higher affinity (Kd = 0.24 microM). Structural studies reveal significant differences in their Hsp90 binding characteristics, and macbecin-induced tumor cell growth inhibition is accompanied by characteristic degradation of Hsp90 client proteins. Macbecin significantly reduced tumor growth rates (minimum T/C: 32%) in a DU145 murine xenograft. Macbecin thus represents an attractive lead for further optimization.

Natural product origins of Hsp90 inhibitors.[Pubmed:14529384]

Curr Cancer Drug Targets. 2003 Oct;3(5):325-30.

The currently used Hsp90 inhibitors, geldanamycin, herbimycin A and radicicol, were isolated many years ago from Streptomyces and fungi originally for their antiprotozoal activity, herbicidal activity and antifungal activity, respectively. In the mid 1980s, it was found that the benzoquinone ansamycin antibiotics (herbimycin A, geldanamycin, and macbecin) reversed v-Src transformed cells to normal phenotypes, and Bcr-abl was subsequently suggested to be the molecular target for the treatment of chronic myelogenous leukemia through a study using herbimycin A for its selective antioncogenic activity. In 1994, these ansamycins were found to bind to Hsp90 and to cause the degradation of client proteins including Src kinases; further efforts to develop anticancer drugs were made using geldanamycin analogs, and 17AAG was chosen as the best candidate for clinical trials. The number of novel natural products isolated from microbial origins is continuing to increase and is doubling every 10 years. Thus, screening of bioactive substances from natural origins, using assays including defined targets, and developing leads toward drugs via optimized derivatization is a conventional but still promising strategy for drug discovery and development.

Antitumor and cytocidal activities of a newly isolated benzenoid ansamycin, macbecin I.[Pubmed:6186564]

Gan. 1982 Dec;73(6):938-44.

Macbecin I showed marked antitumor activity against intraperitoneally (ip) inoculated leukemia P388, melanoma B16, and Ehrlich carcinoma in mice on ip administration. The maximum effect measured in terms of ILS% (increase of life span) was 97 at a daily dose level of 10 mg/kg for leukemia P388, 103 at 5 mg/kg for melanoma B16, and 206 at 10 mg/kg for Ehrlich carcinoma. The effect of Macbecin I on leukemia L1210 was slight (39 ILS%) and no activity was observed against leukemia L5178Y or P388/P-3 (a line of P388 resistant to ansamitocin P-3), or MOPC-104E myloma. Three to six hours after administration of 0.5 mg/kg or more of Macbecin I to mice bearing ascites leukemia P388 cells, typical karyorrhexis followed by cytolysis in P388 cells was observed. Cytocidal changes induced by Macbecin I were also observed in cells which were temporarily prevented from entering mitosis by treatment with known antitumor agents such as 5-fluorouracil, cyclophosphamide, and neocarzinostatin, whereas such cytolysis was not observed in cells which were arrested in metaphase by treatment with ansamitocin P-3. Cytotoxicity of Macbecin I to cultured KB cells was observed at doses of 10(-1) micrograms/ml and more. Reverse transcriptase and terminal deoxynucleotidyl transferase activities were not inhibited by Macbecin I.