Herbimycin ©

1. Discovery1), producing organism1) and structures2-7)
Herbimycins, new benzoquinoid ansamycin antibiotics, were isolated from Streptomyces hygrocopicus AM-3672 and acknowledged as herbicidal agents1). The absolute configuration of herbimycin A was confirmed by X-ray crystallographic analysis3). The total synthesis of herbimycin Awas reported by Tatsuta et al.4) and Yu et al.15)(See Appendix-I).
OO
R2CH3NHO
CH3 H2NCOO
H3COR1CH3 CH3 OCH3R1R22,3)

Herbimycin A
OCH3 OCH3B2,5,6) OHHC7)OH OCH3

Streptomyces hygrocopicus AM-3672

2. Physical data (Herbimycin A)1)
Colorless powder. C30H42N2O9; mol wt 574.30. Sol. in MeOH, EtOH, CHCl3, EtOAc, DMSO,acetone, DMF, benzene. Insol. in H2O, Et2O, hexane.
3. Biological activities1,5,8,9)
1) Herbicidal activity of herbimycin A1,5)
Test plant
Monocotyledon

Dicotyledon

Oryza sativa
Echinochola crus-galli
Digitaria adescendens
Cyperus microiria

Chenopodium ficifolium
Portulaca oleracea
Galinsoga ciliata
Rorippa atrovirens

10025555555Pre-emergencesystem (g/area)
50
25
12.515555555155555540445Post-emergencesystem (g/area)
100502544442) Anti-tobacco mosaic virus activity5)
Antibiotic
Herbimycin A
Herbimycin B
Glendanamicin
Macbecin I

Concentration Inhibition Phytotoxicity(ppm)
(%)
25.0
95
—
12.590—6.292—
3.185—
25.0100—
12.593—
6.288
—
3.158
—
25.099—12.598
—
6.298
—
3.180
—
25.053—000

5545455445543453233) Inhibition of macromolecularsynthesis in ts/NRK cells8)4) Effects on growth and differentiationof human erythroleukemia cells9)

Inhibition (%)

DNARNAProtein

85.5
7.0
11.0

IC50 (ng/ml)

K562 cells
KU812 cells
HEL cells

Hb

24.5
19.1
141.7

2.44
1.63
1.235) Chemical modification and antitumor activity10,11)
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 invivo activity than herbimycin A.
OOOOO
H3COH3COCH3NH

H3CO H CO
3NHO
CH3O
CH3 H2NCOO

H3CO H CO
3CH3 CH3 OCH3Cl

3CH3 CH3 Cl

3OOBrO
H3COCH3NH+NH

O
CH3 H2NCOO

Br3—H3COBrO+O
CH3 H2NCOO
H3CO H CO
3CH3 CH3 OCH3H3COCH3N
H

CH3 CH3 OCH3Herbimycin AO
CH3 Br
H3CO H CO
3OOOO
H3COO
CH3 H2NCOO

H3CO H CO
36Compound
Herbimycin A
12345678CH3NHOCH3CH3 CH3 OCH3H3COCH3 CH3 OCH3H3CO H CO
36.3125250
125
250
125125250
250

1.3 x 525.0 x 550.0 x 5
12.5 x 550.0 x 5
25.0 x 5
25.0 x 550.0 x 550.0 x 5*Number of surviving mice at day 31.

1/4
3/4
4/4
4/4
4/4
1/4
0/4
3/4
2/4

CH3O

CH3 CH3 OCH3T / C Number of*(%) living/total
126
193
215
200
190
134
89200
150

O

8Antitumor activity of herbimycin A derivatives
against Ehrlich ascites carcinomaDose(mg/kg x day)

NH OOCH3OH

7Total dose(mg/kg)

OOO
CH3CH3Bu3SnH, AIBNONAc

NH O

5CuCl

H3COO

CH3 CH3 OCH34Ac2O, AcOAg

3H3CO H CO

BCl3O

H3CO H COO
CH3 H2NCOO

2H2, Pd-C

3CH3NH+Cl

CH3 CH31

H3CO H COO
H3COCH36) Inhibition of tyrosine kinase activity12)
Since herbimycin A appears to exhibit specific inhibitory activity against tyrosine kinases incells, this antibiotic is beneficial in determining whether tyrosine phosphorylation is involved inthe mechanisms for cell transformation, growth, and differentiation.
7) Mechanism of antiproliferative and antitumor activity13,14,16-21)
Herbimysin 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,
thereby promoting degradation of HSP 90 substrates, such as bcr-abl, mutant Flt3 and proteins oftumor angiogenic, apoptosis or ER stress signal transduction pathways16-21).
4. Biosynthesis22)
The biosynthetic gene cluster for herbimycin was identified and the biosynthetic pathway wasproposed. It is synthesized from a 3-amino-5-hydroxybenzoic acid starter unit, followed bypolyketide synthase processing and tailoring enzyme reactions.
5. 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, 6015-6018 (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.		
W. B. Pratt et al., Proc. Soc. Exp. Biol. Med. 217, 420-434 (1998)
14.		
S.-R. Lia et al., J. Biol. Chem., 275, 21850-21855 (2000)
15.		
R. Yan et al., Org. Lett. 16, 3280-3283 (2014)
16. [743] M. Zhao et al., Leukemia 14, 374-378 (2000)
17. [675] E. A. Fisher et al., J. Biol. Chem. 272, 20427-20434 (1997)
18. [610] K. Katagiri et al., J. Biol. Chem. 271, 11557-11562 (1996)
19. [537] S. Sato et al., Leukemia Res. 18, 221-228 (1994)
20. [558] T. Oikawa et al., Biol. Pharm. Bull. 17, 1430-1432 (1994)
21. [570] Y. Honma et al., Int. J. Cancer 60, 685-688 (1995)
22.		
A. Rascher et al., Appl. Env. Microbiol. 71, 4862-4871 (2005)