Andrastin ©

1. Discovery, producing organism and structures1-4)
Andrastins were isolated from the culture broth of a Penicillium simplicissimum strain FO-3929
and found to be protein farnesyltransferase inhibitors. The absolute configuration of the p-bromobenzoyl derivative of andrastin A was elucidated by X-ray crystallographic analysis and itsskeleton was identified as ent-5α,14β-androstane.
H3C

CH3R2CH3R1CH3HO

OOH
CH3CH3OH
OCH3O

HCH3Andrastin ABCDPenicillium sp. FO-3929(Penicillium simplicissimum FO-3929)
Bar: 20 µm

R1R2

CH3COOCH3COOCH3COO

CHO
CH2OH
CH3CH3O

2. Physical data (Andrastin A)
White powder. C28H38O7; mol wt 486.60. Sol. in DMSO, MeOH, CHCl3. Insol. in H2O, hexane.
3. Biological activity2,4,5)
1) Inhibition of protein farnesyltransferase2,4)Protein farnesyltransferase catalyzes the post-translaAndrastin
tional modification of ras p21 that is obligatory for cell		transformation of this oncogene protein.				

IC50 (µM)
ABCD

24.9
47.1
13.3
25.72) Enhancement of drug accumulation in vincristine-resistant KB cells5)
Andrastin A enhanced the cytotoxicity of vincristine 1.5–20 fold in vincristine-resistant KB cells(VJ-300).
120

Growth (%)

10080

Control
Andrastin A (6.25 g/ml)
Andrastin A (12.5 g/ml)
Andrastin A (25 g/ml)
Andrastin A (50 g/ml)

60
40
20
000.010.1
1Vincristine ( g/ml)

103) Other biological activity2)
No antimicrobial activity was shown at a concentration of 1,000 µg/ml against Xanthomonas oryzae KB88, Candida albicans KF-1, Saccharomyces cerevisiae KF26, Mucor racemosus
KF223 (IFO 4581), Pyricularia oryzae KF180, Aspergillus niger KF 103 (ATCC 6275), Staphylococcus aureus KB34 (FDA 209P), Bacillus subtilis KB27 (PCI 219), Escherichia coli KB8(NIHJ), E. coli KB176 (NIHJ JC-2), Pseudomonas aeruginosa KB105 (P3), Micrococcus luteus
KB40 (PCI 1001), Bacteroides fragilis KB169, Mycobacterium smegmatis KB42 (ATCC607), orAcholeplasma laidlawii KB174 (PG8).
4. Biosynthesis3, 7)
The incorporation study of single and double labeled acetate into andrastin A and the result of abiosynthetic study of citreohybridonol, an analog of andrastins, conducted by Kosemura et al.,6)
suggested that andrastins were synthesized as shown below.
A sesquiterpene, synthesized from farnesyl pyrophosphate, is cyclized to form an enantiomerof drimane. 3,5-Dimethylorsellinate derived from tetraketide is combined with drimane to form
ring C. Ring D changes from cyclohexane to cyclopentane by a rearrangement. Thus, an enantiomer of the 5α,14β-androstane skeleton is formed.
Though many compounds produced by fungi from farnesylate and orsellinate have been reported, their absolute structures have not been elucidated. The absolute structures may therefore bedifferent from the reported ones.
The biosynthetic gene cluster for andrastin was identified by Matsuda et al.7)
OHMethionine

CH3COOH
OHO

HOOH

3,5-Dimethylorsellinate

O

OH
OH

A

HO

DOO
OO OH

B

CCOOR

H
O

HO

5. References
1. [605] K. Shiomi et al., Tetrahedron Lett. 37, 1265-1268 (1996)
2. [614] S. Ōmura et al., J. Antibiot. 49, 414-417 (1996)
3. [615] R. Uchida et al., J. Antibiot. 49, 418-424 (1996)
4. [650] R. Uchida et al., J. Antibiot. 49, 1278-1280 (1996)
5. [690] M. C. Rho et al., J. Antibiot. 51, 68-72 (1998)
6.		
S. Kosemura et al., J. Chem. Soc., Perkin Trans. 1 1994, 135-139 (1994)
7.		
Y. Matsuda et al., Tetrahedron 69, 8199-8204 (2013)

O OH