Hymeglusin© (1233A, F-244)

1. Discovery, producing organism and structure1-4)
Specific inhibitors of mevalonate biosynthesis were screened with an intact mammalian cell assay (Vero cells). Hymeglusin (1233A, F-244 or L-659,699) was isolated from the culture brothof Scopulariopsis candida strain F-244 and found to be an inhibitor of Vero cell groth in MEM
medium containing 2% calf serum, but not in the above medium supplemented with 1 mM mevalonate2).
The absolute configuration was determined by Chiang et al.3) The total synthesis of hymeglusin
has been reported by several groups. The first total synthesis was reported by Mori et al.5) (SeeAppendix-I).

CH3 CH3 CH3COOHR RHOO

OHymeglusin (1233A, F-244)

Scopulariopsis sp. F-244(Scopulariopsis candida F-244)
Bar: 5 µm

2. Physical data1)
White amorphous powder. C18H28O5; MW 324.19. Sol. in MeOH, EtOH, CH3CN, EtOAc, CHCl3.
Insol. in H2O, hexane. Store at –20°C.
3. Biological activity1,6–9)
1) Specific and irreversible inhibition of HMG-CoA synthase in vitro6-8) and in vivo9).
CH3CO CoA

Essential for inhibition!!

Acetoacetyl-CoA thiolase
CH3 CH3 CH3CH3COCH2CO CoACoA
H3C

HMG-CoA reductase

COOH

HOHMG-CoA synthase

OOH

HOOC

CO CoA
2NADPHCoA2NADP

H3C
HOOCO
1233A (IC50: 0.20 µM)

Compactin
Mevinolin

OH
CH2OH

cholesterol

2) Mede of action (or Meohanism of action)
Hymeglusin was bound to the active centor 129 Cys of hamster HMG-CoA synthase. It is speculator that the hymeglusin β-lactone ring reacts with the thiol group of the Cys residue as shows
below.

Recemly, X-ray arystalography of hymeglush: HMG CoA synthase complex was defined todemonstrate the speculation was correct.
3) Antimicrobial activity1)
Hymeglusin showed antifungal activity against Candida albicans (MIC: 12.5 µg/ml), Penicillium herquei (25) and Pyricularia oryzae (6.25).
4. Importance of β-lactone geometry for specific HMG-CoA synthase inhibition10–15,17,18)
Two kinds of natural β-lactones have been reported; (2R,3R)-β-lactone as a HMG-CoA synthaseinhibitor and (2S,3S)-β-lactone as a lipase (esterase) inhibitor. During our synthetic study ofβ-lactone analogs, four optically active DU-6622s were synthesized to discriminate between theinhibitory activity of the two. Consequently, (2R,3R)-β-lactone was found to be responsible for
specific inhibition of HMG-CoA synthase, whereas (2S,3S)-β-lactone was responsible for pancreatic lipase inhibition.

2HO

1O

Configuration(C-2, C-3)

3O
DU-6622

COOCH3

(R,R)
(S,S)
(R,S)
(S,R)
(R,R)+(S,S)

IC50 (µM)
HMG-CoA
synthase (H)Pancreaticlipase (L)

0.098
31360
9.4
0.15

270
27>300>300120

5. Biosynthesis16)
2COOH

HOOO

1

CH3COOH[Methyl]methionine

L/H2700
0.87>0.83>328006. References
1. [366] S. Ōmura et al., J. Antibiot. 40, 1356-1357 (1987)
2. [382] H. Tomoda et al., J Antibiot. 41, 247-249 (1988)
3.		
D. C. Aldridge et al., J. Chem. Soc. (C) 3888-3891 (1971)
4.		
Y. C. Chiang et al., J. Org. Chem. 53, 4599-4603 (1988)
5. [440] H. Kumagai et al., J. Antibiot. 43, 397-402 (1990)
6.		
K. Mori et al., Liebigs Ann. Chem. 1991, 1057-1065 (1991)
7. [377] H. Tomoda et al., Biochim. Biophys. Acta. 922, 351-356 (1988)
8. [503] H. Tomoda et al., J. Antibiot. 46, 872-874 (1993)
9. [523] H. Nagashima et al., Life Sci. 52, 1595-1600 (1993)
10. [483] T. Sunazuka et al., J. Antibiot. 45, 1139-1147 (1992)
11. [538] H. Hashizume et al., Chem. Pharm. Bull. 42, 512-520 (1994)
12. [543] H. Hashizume et al., Chem. Pharm. Bull. 42, 1272-1278 (1994)
13. [544] H. Hashizume et al., Heterocycles 38, 1551-1571 (1994)
14. [551] H. Hashizume et al., Chem. Pharm. Bull. 42, 2097-2107 (1994)
15. [480] H. Kumagai et al., J. Antibiot. 45, 563-567 (1992)
16. [661] H. Tomoda et al., J. Org. Chem. 62, 2161-2165 (1997)
17. [737] H. Tomoda et al., Biochem, Biophys. Res. Commun. 265, 536-540 (1999)
18. [858] H. Tomoda et al., Biochem, Biophys. Acta. 1636, 22-28 (2004)