Herbimycin

Discovery(1), producing organism(1) and structure (2-7)

Herbimycins, new benzoquinoid ansamycin antibiotics, were isolated and acknowledged as herbicidal agents (1). The absolute configuration of herbimycin A was confirmed by X-ray crystallographic analysis (3). The first total synthesis of herbimycin A was reported by Tatsuta et al (4).

Physical data (Herbimycin A) (1)

Colorless powder. C₃₀H₄₂N₂O₉; mol wt 574.30. Sol. in MeOH, EtOH, CHC_l3, EtOAc, DMSO, acetone, DMF, benzene. Insol. in H₂O, Et₂O, hexane.

Biological activity (2,4,5)

1) Herbicidal activity of herbimycin A (1,5)

2) Anti-tobacco mosaic virus activity (5)

3) Inhibition of macromolecular synthesis in ts/NRK cells (8)

4) Effects on growth and differentiation of human erythroleukemia cells (9)

5) Chemical modification and antitumor activity (10,11)
Several halogenated and other related derivatives have been synthesized and evaluated in vivo for their activities against Ehrlich ascites carcinoma. Some of these derivatives showed higher in vivo activity than herbimycin A.

6) Inhibition of tyrosine kinase activity (12)
Since herbimycin A appears to exhibit specific inhibitory activity against tyrosine kinases in cells, this antibiotic is beneficial in determining whether tyrosine phosphorylation is involved in the mechanisms for cell transformation, growth, and differentiation.

7) Mechanism of antiproliferative and antitumor (13,14)
Herbimycin A specifically inhibits the cytosolic chaperone HSP 90 and its endoplasmic reticulum (ER) homologue GRP 94. This compound has antiproliferative and antitumor effects: as it binds to HSP 90, it inhibits the HSP 90-mediated conformational maturation/refolding reaction, hereby promoting degradation of HSP 90 substrates.

References

1. [153] S. Ōmura et. al., J. Antibiot., 32, 255-261 (1979)
2. [166] S. Ōmura et. al., Tetrahedron Lett., 44, 4323-4326 (1979)
3. [186] A. Furusaki et. al., J. Antibiot., 33, 781-782 (1980)
4. K. Tatsuta et al., Tetrahedron Lett., 32, 6015 (1991)
5. [193] Y. Iwai et. al., J. Antibiot., 33, 1114-1119 (1980)
6. [207] A. Nakagawa et. al., J. Chem. Soc. Jpn., Chem. & Ind. Chem., 892-894
(1981)
7. [356] K. Shibata et. al., J. Antibiot., 39, 1630-1633 (1986)
8. [397] Y. Uehara et. al., J. Antibiot., 41, 831-834 (1988)
9. [479] Y. Honma et. al., Anticancer Res., 12, 189-192 (1992)
10. [298] S. Ōmura et. al., J. Antibiot., 37, 1264-1267 (1984)
11. [338] K. Shibata et. al., J. Antibiot., 39, 415-423 (1986)
12. Y. Uehara et. al., Methods Enzymol., 201, 370-379 (1991)
13. Pratt, W. B. et. al., Proc. Soc. Exp. Biol. Med. 217, 420-434 (1998)
14. Lia, Supin-Rosa et al. J. Biol. Chem. 275, 21850-21855 (2000)