Chapter 12 Enzyme Inhibitors Produced by Microorganisms

481

Chapter 12 ENZYME INHIBITORS PRODUCED BY MICROORGANISMS HAEiAO UMEZAWA

Institute of Microbial Chemistry

3-14-23 Kamiosaki. Shinagawa.ku.

Tokyo 141. Japan

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485 . . . . . . . . . . . . . . . . . . . . . . . 486 . . . . . . . . . . . . . . . . . . . 486 . . . . . . . . . . . . . . . . . . . . . . . . . . 486 . . . . . . . . . . . . . . . . . . . . . . . . . . 487 . . . . . . . . . . . . . . . . . . . . . . . . . 487 . . . . . . . . . . . . . . . . . . . . . . . . . 487 . . . . . . . . . . . . . . . . . . . . . . . . . . . 488 . . . . . . . . . . . . . . . . . . . . . . . . . . 488 . . . . . . . . . . . . . . . . . . . . . . . . . . . 489 . . . . . . . . . . . . . . . . . . . . . . . . . 489 1.1.9 K-76 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489 1.1.10 E64 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490 1.1.11 Marinostatin . . . . . . . . . . . . . . . . . . . . . . . . 490 1.2 Aminopeptidases . . . . . . . . . . . . . . . . . . . . . . . . 490 Bestatin . . . . . . . . . . . . . . . . . . . . . . . . . . 490 1.2.1 1.2.2 Amastatin . . . . . . . . . . . . . . . . . . . . . . . . . . 491 1.2.3 Actinonin . . . . . . . . . . . . . . . . . . . . . . . . . . 491 1.2.4 Arphamenine . . . . . . . . . . . . . . . . . . . . . . . . . 492 1.2.5 Diprotin . . . . . . . . . . . . . . . . . . . . . . . . . . 492 1.2.6 OF4949 . . . . . . . . . . . . . . . . . . . . . . . . . . . 493 Propioxatin . . . . . . . . . . . . . . . . . . . . . . . . . 493 1.2.7 493 1.3 Carboxypeptidases . . . . . . . . . . . . . . . . . . . . . . . Histargin . . . . . . . . . . . . . . . . . . . . . . . . . . 493 1.3.1 1.3.2 (S)-a-Benzylmalic acid . . . . . . . . . . . . . . . . . . . 494 1.4 Carboxyl proteases . . . . . . . . . . . . . . . . . . . . . . . 494 1.4.1 Pepstatin (=S-PI) . . . . . . . . . . . . . . . . . . . . . . 494 1.4.2 Pepstanone . . . . . . . . . . . . . . . . . . . . . . . . . 495 1.4.3 Hydroxypepstatin . . . . . . . . . . . . . . . . . . . . . . 496 1.5 Angiotensin converting enzyme . . . . . . . . . . . . . . . . . 496 1.5.1 Ancovenin . . . . . . . . . . . . . . . . . . . . . . . . . . 496 1.5.2 L.681. 176 . . . . . . . . . . . . . . . . . . . . . . . . . . 496 1.5.3 Muracein . . . . . . . . . . . . . . . . . . . . . . . . . . 497 1.5.4 I5B2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498 1.5.5 K-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498 Phenacein . . . . . . . . . . . . . . . . . . . . . . . . . . 498 1.5.6 1.5.7 A58365 . . . . . . . . . . . . . . . . . . . . . . . . . . . 498 Foroxymithine . . . . . . . . . . . . . . . . . . . . . . . . 498 1.5.8 1.5.9 K-26 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499 499 1.5.10 Aspergillomarsamine . . . . . . . . . . . . . . . . . . . . . 1.5.11 Ganoderic acid K . . . . . . . . . . . . . . . . . . . . . . 499 1.6 Other metalloproteases . . . . . . . . . . . . . . . . . . . . . 500 1.6.1 Phosphoramidon . . . . . . . . . . . . . . . . . . . . . . . 500 1.6.2 Talopeptin (=MK-1) . . . . . . . . . . . . . . . . . . . . . 500 1.6.3 FMPI . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501

INTRODUCTION 1 INHIBITORS OF PROTEASES 1.1 Serine and thiol proteases 1.1.1 Leupeptin 1.1.2 Antipain Chymostatin 1.1.3 1.1.4 Elastatinal 1.1.5 Elasnin 1.1.6 Streptin 1.1.7 B-MAP1 1.1.8 Thiolstatin

.

482

. . . . . . . . . . . . . . . . . . . . .501 501 . . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 501 502 . . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 502 . . . . . . . . . . . . . . . . . 502 . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 503 503 .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 503 503 . . . . . . . . . . . . . . . . . . . . . 504 504 . . . . . . . . . . . .. .. .. .. .. ... ... ... ... ... ... ... ... ... ... ... ... 504 504 ........ . . . . . . . . . . . . . . . . . . . 505 505 . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 505 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506 . . . . . . . . . . . . . . . . . . . . . . . . . 506 . . . . . . . . . . . . . . . . . . . . . . . . . . 506 . . . . . . . . . . . . . . . . . 506 . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 . . . . . . . . . . . . . . . . . . . . . . . . . 507 3 . INHIBITORS OF OTHER HYDROLASES . . . . . . . . . . . . . . . . . . . 507 3.1 Inhibitors of CAMP phosphodiesterase . . . . . . . . . . . . . . 507 3.1.1 Reticulol . . . . . . . . . . . . . . . . . . . . . . . . . . 507 3.1.2 PDE.1. I1 . . . . . . . . . . . . . . . . . . . . . . . . . . 507 3.1.3 Acylpeptides . . . . . . . . . . . . . . . . . . . . . . . . 508 508 3.1.4 Terferol . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.5 Griseolic acid . . . . . . . . . . . . . . . . . . . . . . . 509 3.2 Phospholipases . . . . . . . . . . . . . . . . . . . . . . . . . 509 3.2.1 N.N '.Ethylenediaminedisuccinic acid . . . . . . . . . . . . . 509 3.2.2 Plastatin. luteosporin . . . . . . . . . . . . . . . . . . . 509 510 3.2.3 Plipastatin . . . . . . . . . . . . . . . . . . . . . . . . . 510 3.3 Alkaline phosphatase . . . . . . . . . . . . . . . . . . . . . . 3.3.1 Forphenicine . . . . . . . . . . . . . . . . . . . . . . . . 510 3.4 Esterase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 511 3.4.1 Esterastin . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2 Ebelactone . . . . . . . . . . . . . . . . . . . . . . . . . 511 3.5 Ribonuclease . . . . . . . . . . . . . . . . . . . . . . . . . . 512 3.5.1 NMP inhibitor . . . . . . . . . . . . . . . . . . . . . . . . 512 3.6 S-Adenosylhomocysteine hydrolase . . . . . . . . . . . . . . . . 512 3.6.1 Neplanocin A . . . . . . . . . . . . . . . . . . . . . . . . 512 3.7 Adenosine deaminase . . . . . . . . . . . . . . . . . . . . . . 512 3.7.1 Coformycin. deoxycoformycin . . . . . . . . . . . . . . . . . 512 3.7.2 2'-Chloropentostatin (ZAdechlorin) . . . . . . . . . . . . . 512 513 3.7.3 Adecypenol . . . . . . . . . . . . . . . . . . . . . . . . . 513 3.8 Adenosine triphosphatase . . . . . . . . . . . . . . . . . . . . 513 3.8.1 Coriolin . . . . . . . . . . . . . . . . . . . . . . . . . . 513 3.8.2 MF722-02 . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8.3 L.681. 110 . . . . . . . . . . . . . . . . . . . . . . . . . . 514 4. INHIBITORS OF OXIDO-REDUCTASES . . . . . . . . . . . . . . . . . . . 514 4.1 Tyrosine hydroxylase . . . . . . . . . . . . . . . . . . . . . . 514 4.1.1 Aquayamycin . . . . . . . . . . . . . . . . . . . . . . . . . 514 4.1.2 Chrothiomycin . . . . . . . . . . . . . . . . . . . . . . . . 514 4.1.3 Deoxyfrenolicin . . . . . . . . . . . . . . . . . . . . . . . 515 4.1.4 Oudenone . . . . . . . . . . . . . . . . . . . . . . . . . . 515 4.2 Dopamine 8-hydroxylase . . . . . . . . . . . . . . . . . . . . . 515 4.2.1 Fusaric acid . . . . . . . . . . . . . . . . . . . . . . . . 515 .

2 INHIBITORS OF GLYCOSIDASES 2.1 Sialidase 2.1.1 Panosialin 2.1.2 Siastatin 2.2 B-Galactosidase 2.2.1 Pyridindolol 2.2.2 Isoflavones 2.2.3 p-Hydroxyphenylacetaldoxime 2.3 a-Glucosidases 2.3.1 Nojirimycin 2.3.2 1-Deoxynojirimycin 2.3.3 Nojirimycin B and D-mannoic-, 6-lactam 2.3.4 S-A1 2.3.5 Valienamine Acarbose and homologues 2.3.6 2.3.7 Trestatin 2.3.8 Oligostatin 2.3.9 AI-A 2.3.10 Amylostatin 2.3.11 Adiposin 2.3.12 Valiolamine and homologues 2.4 Chitinase 2.4.1 Allosamidin

-

483

.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .............. . . . 515 . . . . . . . . . . . . . . . . .. .. .. 516 516 . . . . . . . . . . . . . . . . . . . . 516 . . . . . . . . . . . . . . . . . . . . . 516 . . . . . . . . . . . . . . . . . 516 ...................

4.2.2 Oosponol 4.2.3 Dopastin 4.3 Phenylalanine hydroxylase 4.3.1 3.4.Dihydroxystyrene 4.4 Tryptophan hydroxylase 4.4.1 2.5.Dihydro. L.phenylalanine 4.5 Proline hydroxylase 4.5.1 Vineomycin (~P-1894B) 4.6 Monoamine oxidase 4.6.1 Pimprinine 4.7 Hydroxymethylglutaryl-CoA reductase 4.7.1 ML.236A. B (=Compactin), C. dihydrocompactin 4.7.2 Monacolin K (=Mevinolin). J. L. X. M. dihydromevinolin. dihydromonacolin L 4.8 Aldose reductase 4.8.1 WF3681 4.9 12-Lipoxygenase 4.9.1 3-Methoxytropolone 4.10 Prostaglandin synthetases 4.10.1 Xanthocillin X monomethyl ether 4.10.2 Thielavin A. B

-

.. .. .. 516 516 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517 ...................... . . . 517 . . . . . . . . . . . . . . 517 . . . . . . . . 517

. . . . . . . . . . . . . . . . . . . . . 518 . . . . . . . . . . . . . . . . . . . . . . . . 518 ........................ . . . 518 ..................... . . . 518 . . . . . . . . . . . . . . . . . . . . . 518 . . . . . . . . . . . . . . . . . . . 519 . . . . . . . . . . . . . . 519 . . . . . . . . . . . . . . . . . . . . . . . 519 5. INHIBITORS OF TRANSFERASES . . . . . . . . . . . . . . . . . . . . . 519 5.1 Nonspecific N-methyltransferase . . . . . . . . . . . . . . . . 519 5.1.1 1.[2.(3.4.5.6.tetrahydropyridyl)l.l. 3.pentadiene . . . . . . 519 5.2 Catechol 0-methyltransferase . . . . . . . . . . . . . . . . . . 519 5.2.1 Methylspinazarin. dihydromethylspinazarin . . . . . . . . . . 519 5.2.2 7-0-Methylspinochrome B. 6-(3-hydroxy-n-butyl)-7-0methylspinochrome B . . . . . . . . . . . . . . . . . . . . . 520 5.2.3 Isoflavones . . . . . . . . . . . . . . . . . . . . . . . . . 520 5.2.4 Dehydrodicaffeic acid dilactone . . . . . . . . . . . . . . . 520 5.3 Thymidylate synthetase . . . . . . . . . . . . . . . . . . . . . 521 5.3.1 Vanoxonin . . . . . . . . . . . . . . . . . . . . . . . . . 521 5.3.2 Diazaquinomycin . . . . . . . . . . . . . . . . . . . . . . . 521 5.4 Glucosyltransferase (dextransucrase) . . . . . . . . . . . . . . 521 5.4.1 Ribocitrin . . . . . . . . . . . . . . . . . . . . . . . . . 521 5.5 Asparate aminotransferase . . . . . . . . . . . . . . . . . . . 522 5.5.1 Gostatin . . . . . . . . . . . . . . . . . . . . . . . . . . 522 5.6 Ornithine-ketoglutarate aminotransferase . . . . . . . . . . . . 522 5.6.1 Gabaculine . . . . . . . . . . . . . . . . . . . . . . . . . 522 5.7 Glutamine amidotransferase . . . . . . . . . . . . . . . . . . . 522 5.7.1 Acivicin (AT-125) . . . . . . . . . . . . . . . . . . . . . . 522 5.8 Tyrosine protein kinase . . . . . . . . . . . . . . . . . . . . 522 5.8.1 Erbstatin . . . . . . . . . . . . . . . . . . . . . . . . . . 522 5.9 Reverse transcriptase . . . . . . . . . . . . . . . . . . . . . 523 . . . . . 523 5.9.1 Retrostatin . . . . . . . . . . . . . . . . . . . . . . . . . 523 5.9.2 Limocrocin . . . . . . . . . . . . . . . . . . . . 5.9.3 Sakyomicins . . . . . . . . . . . . . . . . . . . . . . . . . 523 5.10 Aminoglycoside 2"-O-adenyltransferase . . . . . . . . . . . . . 524 5.10.1 7-Hydroxytropolone . . . . . . . . . . . . . . . . . . . . . 524 6. INHIBITORS OF LYASES . . . . . . . . . . . . . . . . . . . . . . . . 524 6.1 Glutamate decarboxylase . . . . . . . . . . . . . . . . . . . . 524 6.1.1 4.5.Dihydroxyisophthalic acid . . . . . . . . . . . . . . . . 524 6.2 Histidine decarboxylase . . . . . . . . . . . . . . . . . . . . 524 524 6.2.1 Lecanoric acid . . . . . . . . . . . . . . . . . . . . . . . 6.3 Dopa decarboxylase . . . . . . . . . . . . . . . . . . . . . . . 524 6.3.1 Isoflavones . . . . . . . . . . . . . . . . . . . . . . . . . 524 6.4 Fumarase . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525 6.4.1 S.2. 3.Dicarboxyaziridine . . . . . . . . . . . . . . . . . . 525 6.5 Glyoxalase I . . . . . . . . . . . . . . . . . . . . . . . . . . 525 0

484

525 . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 525 526 7 . INHIBITOR OF LYGASES . . . . . . . . . . . . . . . . . . . . . . . . 526 7.1 Acetyl CoA carboxylase . . . . . . . . . . . . . . . . . . . . . 7.1.1 Decanyl-1-petenedioic acid . . . . . . . . . . . . . . . . . 526 8 . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527 6.5.1 6.5.2

Glyo-I1 MS-3

485

INTRODUCTION In animals and plants, enzymes and their inhibitors often coexist, and these inhibitors are macromolecular peptides.

In contrast, as shown in this

article, microorganisms produce low-molecular-weight enzyme inhibitors and release them extracellularly. In 1966, the screening of microbial culture filtrates for enzyme inhibitors was initiated by this author, who reported the first discovery in 1969 of low-molecular-weight enzyme inhibitors produced by a streptomyces strain. Since then, more than 70 inhibitors have been reported. Their structures were elucidated, most of them were chemically synthesized, and new types of inhibitory structures were disclosed. The discoveries made up to 1 9 7 2 have been described in an earlier review. 1) The number of inhibitors and the varieties of their structure prohibit detailed description in contrast to the earliest review. The purification schemes of only 2 4 inhibitors are described. It is often said that the reason microorganisms in nature produce antibiotics is to suppress the growth of their competitors. However, most enzyme inhibitors produced by microorganisms have no significant antimicrobial activity. The discovery of low-molecular-weight inhibitors indicates that microorganisms produce compounds of various structures which may play no role in the growth of the cells producing them.

As later described, it has been shown

that leupeptin (a protease inhibitor) has no function in the cells producing it. Among the inhibitors included in this review, 88 were extracted from the culture filtrate and 17 were from the mycelium or the whole broth.

This ratio

is 32 versus 2 in cases of proteases. These facts suggest the generally extracellular abundance of inhibitors.

As shown by the production of antibiotics and enzyme inhibitors, microorganisms are a veritable treasury of organic compounds which have various structures and pharmacological activities. Therefore, the success of determining the presence of the target products in culture broths is dependent upon the testing method.

A s described in an early review,')

the quantity of an

inhibitor is obtained by measuring the reaction product (a) in the reaction mixture without inhibitor and the product (b) in the mixture with inhibitor, and calculating the percent inhibition by (a-b)/a x 100.

It is interesting to note that inhibitors can be found, but stimulators have not as yet been found.

The author and Dr. Nagatsu, Biochemistry Depart-

ment of the Medical School of the University of Nagoya searched for a stimulator of phenylalanine hydroxylase exhaustively, but were not successful. However, the search for an antagonist of an endogenous inhibitor of a certain enzyme may lead to the finding of a compound which augments the activity of the enzyme in vivo.

486

Besides an earlier review,’) there are others; in one2) inhibitors discovered before 1982 are described; and in the other two314) protease inhibitors discovered before 1976 or before 1983 are described. As described in these reviews, most inhibitors have been discovered in culture filtrates of actinomycetes, bacteria and fungi.

1.

INHIBITORS OF PROTEASES

1.1

Inhibitors of Serine and Thiol Proteases

1.1.1

Leupeptin Structure:5) CH

1 3

CH

1 3

NH 1 2 C=NH I

YH

CH-CH3 CH-CH3 I I y 2 YH2 (YH2)3 R-CO-NH-CH-CO-NH-CH-CO-NH-CH-CHO (Sl (S1 (S) R=CH3 (or C2H51

Active against: plasmin, trypsin, papain, thr~mbolcinase,~)dipeptidyl aminopeptidase I1111) Producing organism: Streptomyces roseus,

I

2.

roseochromogenes

Isolation: Culture filtrate Lewatit CNP (Na 50%, H 50%) adsorption eluted with 1N HC1 in 80% methanol

Active eluate neutralized

1

evaporated in vacuo

Brownish crude powder I

1

extracted with n-butanol evaporated in vacuo

Brownish crude powder I1

1

Dowex 1-X2 (Cl) column chromatography developed with H20 lyophilized

White powder, leupeptin6.7) Chromatography: Separation of the acetyl and propionyl forms of leupeptin was performed in their di-n-butyl acetal-form on silicic acid column. TLC, silica gel G and BuOH-BuOAc-AcOH-H20 (4:Z:l:l)

showed two spots (Rfc0.33 and

0.40) , depending on the two ta~tomers.~) A Sepharose bound leupeptin-like peptide aldehyde (Seph-GlyGlyArgal) was used as an affinity adsorbent for

487

trypsin.8)

The amino acid sequence of leupeptin was analysed with fast atom

bomberdment mass spectrometry.’)

Plasma leupeptin level was assayed using

the reversible binding of leupeptin to bovine trypsin. lo) In a biosynthetic study, the final enzyme (leupeptin acid-reductase) was found to firmly bound to the cell membrane and the resulting product leupeptin to be released out avoiding the accumulation and interference with normal protein turnover. 12) Leupeptin is undergoing clinical investigation in the field of microsurgical nerve repair. 13) 1.1.2

Antipain Structure:14) y 2 C=NH I y

YH

CH

1 3

(YH213

2

YH-CH3

YH2 C=N H I NH

I

(YH213

HOOC-CH-NH-CO-NH-CH-CO-NH-CH-CO-NH-CH-CHO (S 1 (51 (S 1 I S1

Active against: trypsin, papain, thrombokinase15) Producing organism:

1.1.3

Streptomyces michigaensis,

2.

yokosukaensis

Chymostatin Structure:16)

CH-CH3 I FH2 FH2 YH2 HOOC-t~-NH-CO-NH-CH-CO-NH-CH-CO-NH-CH-CHO (S I (S I 6) (S1

Active against: a-chymotrypsin, B-chymotrypsin, y-chymotrypsin, 6chymotrypsin, papain 17) Producing organism:

--

ensis, S . hygroscopicus,

1.1.4

Streptomyces

2.

, 2.

lavendulae

Elastatinal Structure:18) FH3

CH-CH.,

YONH2

;.”:

H;$( y 3 y 2 HOOC-CH-NH-CO-NH-CH-CO-NH-CH-CO-NH-CH-CHO (SI (5 1 (S1 (S1

argenteolus var. toyonaka-

488

Active against:

pancreatic elastase

Producing organism:

1.1.5

19)

Streptomyces griseoruber

Elasnin Structure..20)

granulocyte elastase 21)

Active against:

Producing organism: Streptomyces noboritoensis

I

Isolation: Whole broth extracted with ethyl acetate and evaporated extracted with benzene and evaporated Silica gel chromatography with benzene-acetone

Dark red oil

1 1

alumina (neutral) chromatography with benzene-ethyl acetate

Brown oil Silica gel (acetate buffer-treated) chromatography with benzene-ethyl acetate

I

Yellow oil Silica gel chromatography with benzene-ethyl acetate

Pale yellow oil

1

Silica gel preparative thin layer Chromatography with benzene-ethanol

Colorless oil, elasnin

1.1.6

Streptin22) Structure: YH2 C=NH I y 3

YH

::$CH-CH~-CO-NH-CH-CO-NH-CH-CO-NH-CH-CHO FH2 CH-CH3 I. (fH2)3

Active against:

trypsin, calpain (CANP)

Producing organism:

, papain

Streptompces tanabeensis

489

1.1.7

6-MAP1

Structure:23) YH2

C=NH I

YH

CH I 2

CH

1 3

CH-CHJ 1

(FH2)3

Q CH

1 2

HOOC-CH-NH-CO-NH-CH-CO-NH-CH-CO-NH-CH-CHO

Active against: subtilisin, other alkaline proteinases, a-chymotrypsin, papain, ficin, bromelain, cathepsin B 24) Producing organism: Streptomyes nigrescens25) 1.1.8 Thiolstatin26)

Structure: H2N-C=NH

FsH5 0 II FH2 CH3C-NH-CH-C-N

f

I

NH I (FH2)3 H-C H-C HO

Active against: papain, ficin, clostripain, trypsin Producing organism: Bacillus cereus 1.1.9

K-76 Structure:27)

Active against: complement enzymes28) Producing organism: Stachybotrys complementi nov. sp. K-76 Isolation: Culture filtrate methanol extraction Amberlite XAD-2 chromatography with ethyl acetate carbon decolorization Sephadex LH-20 chromatography with chloroform-ethyl acetate (1:l vol.) concentrated and diluted with n-hexane Precipitate, K-76

490

1.1.10 E64 *29) Structure. CH~CHCH~CHCONH(CH~) ,,NHCNHZ (!Hj

YH I

,CH 'CHCOO

0 1

RH

H

30,311

Active against: ficin, bromelain, papain, CANP

Producing organism: Aspergillus japonicus TPR-64

1.1.11 Marinostatins32) Structure: Peptides of molecular weights 1500 (B-2, C-2) or 1700 (B-1, c-1).

Active against: Subtilisin, a-chymotrypsin Producing organism: Alteromonas SP. B-10-31 1.2 1.2.1

Inhibitors of Aminopeptidases Bestatin Structure..33)

Active against: leucine aminopeptidase, aminopeptidase B; especially on cell surface34)

Producing organism: Streptomyces olivoleticuli35) Isolation: Culture filtrate n-butanol extraction Dowex 50W-X8 chromatography with pyridine-acetic acid system Sephadex LH-20 chromatography Silica gel chromatography with butyl acetate-n-butanolacetic acid-water system

gas chromatography mass spectrometry at a sensitivity of 1 ng per ml in human serum.36) A high performance liquid chromatography with fluorescence labeling is available as a conventional method at a sensitivity of 100 ng per ml. 37) Bestatin is under clinical investigations in the fields of leukemia, melanoma, squamous cell carcinoma of head and neck, esphageal cancer and bladder cancer.38,39)

49 1

1.2.2

Amastatin Structure..40) N H OH #~$CH-CH~-CH-CH-CO-L-V~I-L-V~I-L-AV 1 2 1 (R)

(5)

Amberlite XAD-4 chromatography with 50% methanol Dowex 1-X4 chromatography with 0.1N acetic acid D U E Sephadex A-25 chromatography with pyridine-acetic acid Dowex 50W-X4 chromatography with pyridine-formic acid system Silica gel chromatography with butyl acetate-n-butanolacetic acid-water Dowex 50W-X4 chromatography with pyridine-formic acid Dowex 50W-X4 chromatography with 0.2N ammonia

1.2.3

Actinonin Structure: 43)

Active against: aminopeptidase M, leucine aminopeptidase44) Producing organism: Actinomycetes MG848-hF6 Isolation: Culture filtrate Amberlite XAD-4 chromatography with 80% methanol silanized Silica gel (equilibrated with 1% citrate and 2% potassium acetate buffer, pH 4.9) chromatography with a linear gradient of acetonitrile from 0 to 50% in the same buffer Amberlite XAD-4 chromatography with 80% methanol

I

Light brownish powder Silica gel chromatography with chloroform-methanol (95:5) recrystallization with methanol-benzene

Act inonin

492

1.2.4

Arphamenine A and B Structure:45)

/y F1?H

H2y

A : R=H,

P

0 : R=OH

Active against: aminopeptidase A, aminopeptidase B46) Producing organism: Chromobacterium violaceum A biosynthetic study of arphamenine A suggested the final step to be the methylene ketone bondage formation by a unique enzyme and a resulting decarboxylation in the arginine moiety. 47) 1.2.5

Diprotin A and B 48) Structure:

0

R H3C$

H2NCH-CO-N

T2

CONHCHCOOH

A:

R1 CH2CH3

R2 CH(CH3)CH2CH3

0:

CH3

CH2CH(CH3)CH3

Active against: dipeptidyl aminopeptidase IV Producing organism: Bacillus cereus BMF673-RF1 Isolation: Culture filtrate carbon adsorption and elution with 90% methanol adjusted pH 2.0 with HC1 Dowex 50W-X8 chromatography with 1.5N ammonia Dowex 50W-X4 chromatography with pyridine-acetate buffer Sephadex 6-25 chromatography Silica gel 60 chromatography with ethanol-28% (w/v) ammonia (50: 1) Dowex 50W-X4 chromatography with 0.2 M pyridineacetate buffer (pH 3 . 2 )

1

Two active fractions Silica gel 60 Chromatography with chloroformmethanol-acetic acid-water (60:8:2:1) Dowex 50W-X4 with 0.2 M pyridine-acetate (pH 3.2) desalted with Dowex 50W-X4 (H) and IN ammonia

Diprotin A and B (colorless powder)

493

1.2.6

OF4949 structure :49) ?R1

NH CO \ / CH I

CH-R2 I

CO-NH2

OF4949-11 :

R =OH 2 R,=H, R2=OH

OF4949-111:

Rl=CH3, R 2 = H

OF4949-IV:

R =H, R =H 1 2

OF4949-1

Active against:

arninopeptidase A 50)

Producing organism: 1.2.7

Rl=CH3,

:

Penicillium rugulosum OF4949

Propioxatin Structure:51)

R

\I

CH3

CH

A : R=H,

Active against:

H3C\/CH3 CH I 0 : R=CH

3

aminopeptidase-I, -11 and M, Leu-aminopeptidase, enke-

phalinase B 52) Producing organism:

1.3. 1.3.1

Kitasatosporiasetae SANK60684

Inhibitors of Carboxypeptidases Histargin Structure: 53) H2N- C=NH t H y 2 FH2 y 2 y 2 HOOCCHNHCH2CH2NHCHCOOH (S 1 (S 1

494

Active against: carboxypeptidase B54) Producing organism: Streptomyces roseoviridis MF118-A5 Isolation: Culture filtrate Amberlike IRC-50 chromatography with 0.5N HC1 in 50% acetone carbon adsorption and elution with 50% acetone pH adjusted 2 with HC1 Dowex 50W-X4 chromatography with 1 M pyridine-acetate buffer (pH 5.0) preparative HPLC (Partisil-lO-ODS-3/Magnum 20) with 10% ammonia Dowex 50W-X4 adsorption and elution with 1.5N ammonia 1

lorless powder, histargin 1.3.2

(S)-a-Benzylmalic Acid 55) Active against: carboxypeptidase A, carboxypeptidase B Producing organism: Streptomyces hydroscopicus MG368-CF16

1.4. 1.4.1

Inhibitors of Carboxyl Protease Pepstatins and S-PI (Pepsin Inhibitor from Streptomyces) Structure:56-59)

FH3 CH-CH3 I

y 3 CH-CH3 I

CH 1 3 CH-CH3 I

CH2 I O t H

C1 H 3

7H3 CH-CH3 I 7H2

y

RCO-NH-CH-CO-NH-CH-CO-NH-CH-CH-CH2-CO-NH-CH-CO-NH-CH-CH-CH2-COOH (SI (S 1 (S) (S1 6) ( S ) (S1

Pepstatin A

: R=CH2CH(CH3)CH3

8 : R=CH2CH2CH2CH2CH3 C : R=CH2CH2CH(CH3)CH3

S-PI or Ac: R=CH3 Pr : R=CH2CH3 Bu : R=CH2CH2CH3

Active against:

pepsin, protease B of Aspergillus

e, acid protease

of Trometes sanguinea, acid protease of Aspergillus saitoi, acid protease of

Xylaria sp., renin, cathepsin D, Mucor rennet, Rhodotorula protease, Saccharomyces protease60-63) Producing organism: Streptomyces testaceus Hamada et Okami,

S.

argenteolus var. toyonakaensis, Streptomyces naniwaensis, Streptomyces No. 2907, S . parvisporogenes64)

495

II

Isolation: Culture filtrate

(5.

testaceus)

n-butanol extraction lyophilized, dissolved in methanol carbon treatment at 40°C and cooled

Crystals, pepstatin recrystallization

Pepstatin A

I

Isolation: Culture filtrate

(5. parvisporogenes)

carbon adsorption and methanol extraction carbon chromatography with 70% propanol

White powder (pepstatin Bu, Pr and Ac)

_1

Amberlite XAD-2 chromatography with 60% methanol Silica gel column chromatography with chloroformmethanol-acetic acid (96:6:2)

Pepstatin Ac

Pepstatin Bu and Pr

11

Silica gel column chromatography with n-butanolpyridine-acetic acid-water (1OO:l:l:l)

Pepstatin Bu and Pr Chromatography: TLC, silica gel and chloroform-methanol-acetic acid (95:4:1) of methyl esters, gives two spots: pepstatin B and C. (lOO:l:l:l),

Bu (0.61).

Rf 0.35 pepstatin A and Rf 0.39

TLC, silica gel and n-butanol-pyridine-acetic acid-water

gives Rf-values: pepstatin A (0.651, Ac (0.40), Pr (0.51) and Renin was purified by affinity chromatography using a pepstatin

column.65366) Pepstatin, labelled with bimane, biotin or dinitrophenyl group is used to localize cathepsin D.67-69) Pepstatin analogues containing statine 3-methylstatine or difluorostatine have been synthesized to obtain inhibitors of renin or pepsin. 70-74) (4-amino-3-hydroxy-6-methylheptanoic

1.4.2

acid (3S,4S)),

Pepstanone75) Structure: y 3 C1 H 3 FH3 CH-CH3 CH-CH3CH CH-CH3 I I 3 YH3 I FH2 VH-CH, FH-CH3 FH2 YH FH3 FH2 CO-NH-CH-CO-NH-CH-CO-NH-CH-CH-CH2-CO-NH-CH-CO-NH-CH-C-CH3

P

Active against: pepsin Producing organism: minor component of pepstatin Chromatography: TLC, silica gel and chloroform-methanol-acetic acid (92.5:6:1.5)

gives Rf-values:

pepstanone (0.45) and pepstatins (0.15).

496

1.4.3

Hydroxypepstatin76) Structure: CH 1 3 CH-CH3

CH 1 3

7H3

y 3 CH-CH3 I

CHI YH I RCO-NH-CH-CO-NH-CH-CO-NH-CH-CH-CH~-CO-NH-CH-CO-NH-CH-CH-CH~-COOH (iH20H

I

R =

E!~H-cH~-

Active against: pepsin, cathepsin D, renin Producing organism: Streptomyces testaceus 1.5 Inhibitors o f Angiotensin Converting Enzyme 1.5.1 Ancovenin77) Structure: peptide composed of 16 amino acid residues containing

e-

B-methyllanthionine, m=-lanthionine and dehydroalanine Producing organism: Streptomyces sp. No. A647P-2 Isolation: Culture filtrate

I I

Diaion HP-30 chromatography with 0.01N HC1 in methanol CM-Sephadex C-25 (0.1 M acetate buffer, pH 2.5) chromatography with 0.3 M NaCl Diaion HP-30 chromatography with methanol CM-Sephadex C-25 ( 0 . 1 M acetate buffer, pH 4.8) chromatography with water, and lyophilized

Brown powder hberlite XAD-11 chromatography, with 20% acetonitrile

I

Crude ancovenine CM-Sephadex C-25 (0.1 M acetate buffer, pH 4.8) chromatography Bio-gel P-2 chromatography

Ancovenin 1.5.2

L-681,176 ~tructure:~~) HOOC HOOC+-#

COO H

OH

L+, NH

497

Producing organism:

i

Streptomyces sp. MA5143a 7 9 )

Isolation: Culture filtrate adsorbed on Dowex-50 (NH ) at pH 3.5, washed with 4 H20 and eluted with 2% pyridlne adsorbed on Dowex 50-X4 (pyrldlne acetate, pH 3.0-3.5) stepwlse elution with pyridlne acetate buffer of Increasing pH

pH 4.0-4.5 eluate Crystal, L-681,176 1.5.3

Muraceins Structure

I

R

(Alas Ala, Diaminopimelic acid,

*O *i f

OH

Muracein

COCH3

GIU,

Ser)

C

81) Producing organism: Nocardia orientalls Isolation: Culture filtrate carbon chromatography with 50% acetone Bio-Rad AG1-XZ (acetate) chromatography with a linear gradient of pyridine-acetic acid (0-0.25 M) MCI gel (HP2OP with a linear gradient of acetone (0-66%)

.c-

~

Muracein A

t

Muraceins A+C

4

Muracein B

MCI gel CHPZOP chromatography with H20 Muracein A

Muracein C

HPLC-retention times (minutes), on C18 spherical packed column with 10% CH CN, 0.1% 1-heptanesulfonic acid sodium salt in water, isocratic, pH 2.1 3 with HC1, 1.5 ml/min and 210 nm, are for muraceins A, B and C 6.2 ( c I ) , 6.9 80) (B), 9 . 7 (a), 11.9 (6) and 8.5 (a), 10.0 (6) respectively.

498

Structure: peptlde composed of N-methylvallne, tyroslne and l-amlno-2acid

(4-hydroxypheny1)ethylphosphonic

Producing organism:

Actinomadura sp. No. 937ZE-1

TLC-Rf's on cellulose plate and n-butanol-AcOH-H20 (4:l:l) are 0.38 for I5B2 and 0.52 for I5B1 (which Is Identical to K-4). 1.5.5

383)

Structure: peptide containing (R)-l-amino-2-(4-hydroxyphenyl)ethylphosphonic acid as the C-terminal Producing organism: Actlnomadura spiculosospora nov. sp. K-4 1.5.6

Phenacein ~tructure:~~) OH

COO H

Producing organism: Streptomyces tanas 1.5.7

insis-zaomycetlcus85)

A58365A and B Structure :86)

HOOC

HOOC COO H

COOH A

6

Producing organism: Streptomyces chromofucus87) 1.5.8

Foroxymithine88) Structure: H C=O I

ti40 H

FH2 y 2

0

FHz CH20H I C H gCO NHC HCO N HCHCO N ( C H2) S

AH

0

499

Producing organism: Streptomyces nitrosporeus

I

Isolation: Culture filtrate carbon chromatography with 50% acetone DUE-Sephadex A-25 (C1) chromatography silanized silica gel 60 chromatography preparative HPLC, nucleosil 5C18 with methanol0.4% acetic acid (1:9)

Foroxymithine 89)

K-26 -

1.5.9

Structure: peptide, composed of L-isoleucine, L-tyrosine and l(R)-1amino-2-(4-hydroxyphenyl)-ethylphosphoric acid Producing organism: Actinomycete K-26

precipitated with CaC12, Ca (PO4 ) 2 and acetone dissolved in water at pH 9.3 Amberlite IRC 50 (NH4) chromatography with water crystallized at pH 3.0 1 Aspergillomarasmine A

1.5.11

Ganoderic Acid K92)

Structure:

Producing organism: Ganodema lucidum

crystallized at pH 2.5

500

1.6

Inhibitors of Other Metalloproteases

1.6.1

Phosphoramidon Structure.*93)

CH CH \3/

3

$H

CH PH fH2 1 2 o .&P-NH-CH-CO-NH-CH-COOH (Sl (S1

carbon adsorption and elution with methanol at pH 8.0 DEAE-Sephadex A-25 chromatography with a linear gradient of NaCl (0-1.0 M) in 1 M acetic acid ethanol extraction Sephadex LH-20 chromatography with methanol

1.6.2

Talopeptin (MK-1) Structure.-97)

'

y

2

0 +P-NH-CH-CO-NH-CH-COOH

?

(5)

(S 1

Active against: thermolysin, elastase98) Producing organism: Streptomyces mozunensis

Isolation: Culture filtrate carbon adsorption and elution with 0.1 M ammonia in 70% methanol n-butanol extraction at pH 2 DEAE Sephadex A-25 chromatography with a linear gradient of NaCl (0-0.5 M) in 1 M acetic acid carbon chromatography with 90% methanol at pH 10.5 Sephadex G-10 chromatography White powder, talopeptin 1.6.3

FMpI Structure: composed of L-phenylalanyl-L-arginine and phosphoric acid99) Active against:

thermolysin, microbial metallo-proteases Streptomyces rishiriensis100)

Producing organism:

Isolation: Culture filtrate

I

Dowex 1-X2 (OH-) chromatography with 0.5 M K2C03 methanol extraction aluminum oxide chromatography with chloroformmethanol-water (2:8:3) and later 0.01N NaOH Dowex 1-X2 (OH ) chromatography with 0.5 M K2C03 Amberlite XAD-2 chromatography with 3 M NaCl and later 0.01N NaOH methanol extraction Cellulofine GC-25 chromatography with ethanol-0.01N NaOH (8:2 to 6:4) Sephadex LH-20 gel filtration with ethanol-0.01N NaOH evaporated in vacuo and active ingredient is precipitated with ethanol

ite powder, FMPI 2.

INHIBITORS OF GLYCOSIDASES

2.1

Inhibitors of Sialidase

2.1.1

Panosialin 101)

Structure:

SO 3K

I

bR n

Active against:

/CH3 - ( C H ) -CH 'CH3

'"

n=12,13

or

sialidase, acid phosphatase. polygalacturonase102)

Producing organism: panos l a1inus

R =

Streptomyces pseudoverticillus nov. sp.,

2. rimosus

502

2.1.2

103) Siastatin Structure:

OH

OH

Active against: sialidase, B-glucuronidase, N-acetyl-B-D-glucosaminidase Producing organism: Streptomyces verticillus var. quintum Isolation: Culture filtrate Amberlite IR-120 (H) adsorption and elution with 1N NH OH Silica gel chromatography with n-butanol-acetic acid- 4 water (4: 1: 1) Avicel chromatography with 70% n-propanol Avicel chromatography with n-butanol-acetic acidwater (4:l:l) Dowex 5OW-XZ chromatography with pyridineformic acid buffer

J

Siastatin A-fraction

t

Dowex 1-X2 chromatography with a gradient of pyridine-acetate buffer (8%-20%) siastatin A 2.2

2.2.1

I

Siastatin B-fraction dissolved in water and precipitated with methanol

Siastatin B

Inhibitors of 6-Galactosidase Pyridindolol Structure:104)

Active against: B-galactosidase105) Producing organism: Streptomyces alboverticillatus

503

2.2.2

Isoflavones 106) Structure:

II : 0-rhm 111-1 : (genistein)

OH

111-2 : 0 - r h m 111-3 : 0 - r h m

IV-1 : IV-2

OH

: 0-rhm

H OH H OH

0-rhm

OH OH

0-rhm

H

OH

OH

OH

r h m = rhamnosyl

107) Active against: 6-galactosidase Producing organism: Streptomyces xanthophaeus 2.2.3

108) p-Hydroxyphenylacetaldoxime Active against:

6-galactosidase

Producing organism: Streptomyces nigellus MD824-CG2 2.3

Inhibitors of a-Glucosidases

110,111) Active against: a-glucosidases, 8-glucosidases Producing organism: Streptomyces roseochrornogenes R-468,

SF-425 109)

2. lavendulae

112) Isolation: Culture filtrate decolorization with carbon at pH 2 passed through an Amberlite IR-45 (OH) column, adsorbed on Dowex 50 (H) and eluted with aq. ammonia washed with n-butanol Dowex 50-X8 chromatography with dil. ammonia Dowex 1-X2 (OH) chromatography with water freeze-dried N o j irimycin

504

2.3.2

1-Deoxynojlrimycln 113)

Structure:

Hoe% HO

Active against:

a-glucosidases, 6-glucosldases

Producing organism: (DMS365), 2.3.3

114,115)

Bacillus amylollquefaclens (DMS7),

polymyxa

g. subtills (DMS704), Streptomyces lavendulae SF-425

Nojlrlmycln B and D-mannonlc-6-lactam

116)

Structure: HOH2C OH

HO

Nojirimycin B

Active against:

0

-O H

OH

D-mannonic-d-lactam

a-mannosidase, 6-glucosldase

Producing organism:

Streptomyces lavendulae 81-425

Co-produced with nojirlmycln.

Two were separated with fractional crystal-

lization of blsulflte adducts, where nojlrlmycln was recovered at first.

S-AI

2.3.4

(Glucose)5-(S-AI-X)-(reduclng 117) I s common to amylostatln (2.3.10) 118) Active against: a-amylase Structure:

Producing organism:

Glucose residue)

Note:

S-AI-X

Streptomyces dlastatlcus var. amylostatlcus No.

2476119) 2.3.5

Valienamlne

120)

Structure:

Active against:

a-glucosidase, 6-glucosldase

Producing organism: phllum

Pseudornonas denltriflcans, Flavobacterium saccharo-

505

2.3.6

Acarbose and Homologues Structure:

121)

H

OH OH OH The general formula o f pseudo-oligosaccharide a-glunosidase inhibitors. Acarbose: m=O, n=2

Active against: a-glucosidases (sucrase, maltase, amylase) Producing organism: Actinoplanes Isolation:

I

Culture filtrate carbon absorption and desorption with aq. ethanol Dowex 50W-X4 (H) chromatography with a linear gradient of NaCl (0-0.13 M) in mM HC1

Acarbose Acarbose is under clinical investigations for obesty and type I and I1 diabetes. 122) 2.3.7

Trestatin Structure: 123) r

3

Active against:

n Trestatin A (n=2) I' B (n-1) " C ln=31 a-amylase 124)

Producing organism:

Streptomyces dimorphogenes NR-320-OM7HB

Ro 09-0766, -0767 and -0768, which are maltosylated trestatin C, A and B

respectively are reported.1 2 5 ) 2.3.8

Oligostatin Structure: 126)

CH, OH

OH

Oligostatin C (lc): m=O, n=2 Oligostatin D ( I d ) : m=O, n=3 Oligostatin E (le) : m = l , n=3

OH

H

506

Active against:

a-amylase

Producing organism:

127)

Streptomyces myxogenes nov. sp, SF-1130

128)

2.3.9

Structure:

1300-1500 Dalton oligosaccharide with one free amino group.

Active against:

glucoamylase, a-amylase, phosphorylase a-type

Producing organism: 2.3.10

Amylostatin

Structure:

Streptomyces flavochromogenes

129)

(Glucose)5-(S-AI-X)

Note:

S-AI-X i s a nitrogen-containing

compound Active against:

a-amylase, glucoamylase

Producing organism:

Streptomyces diastaticus subsp. amylostaticus No.

2476 2.3.11

Adiposin 130)

Structure:

CHIOH

\

HO

Active against:

a-glucosidases

Producing organism: 2.3.12

131)

Streptomyces calvus TM-521

Valiolamine and Homologues

Structure:

PH

FH20H

I

bH Valiolamine Active against:

FH20"

OH

Epivaliolamine a-glucosidases

Producing organism:

Deoxyvalidamine 132,133)

Streptomyces hygroscopicus subsp. limoneus

Epivaliolamine and deoxyvalidamine, of less potency, were co-produced.

Rf values (n-propanol-acetic acid-water, 4 : l : l ) of TLC are: (0.27),

epivaliolamine (0.401, deoxyvalidamine ( 0 . 4 5 ) .

valiolamine

507

2.4

2.4.1

Inhibitor of Chitinase Allosamidin 134) Structure:

OH

OH

Active against:

OH

chitinase

Producing organism: 3.

"

NHAc

Streptomyces sp. No. 1713

INHIBITORS OF OTHER HYDROLASES

3.1

Inhibitors of CAMP Phosphodiesterase

3.1.1

Reticulol 135) Structure:

OH 0 Active against:

CAMP phosphodiesterase 136)

Producing organism: 3.1.2

PDE Structure:

Streptomyces mobaraensis MD611-C6

137)

R-C-N

HO OCH3

PDE-I : R = N H 2

PDE-II : R=CH3

Active against:

CAMP phosphodiesterase

Producing organism:

138)

Streptomyces griseoflavus MD769-C6

CH3

508

Compound

R

V

CH3CH C H ( C H 2 1 8 21 CH 3

Active against:

140)

CAMP phosphodiesterase

Producing organism: Bacillus subtilis C-756 Isolation: Culture filtrate precipitation with HC1 or CuS04 extraction with ethyl acetate Sephadex 6-50 chromatography with tris-HC1 (pH 7 . 5 ) Silica gel 60 column chromatography with chloroform-methanol (8:1) Sephadex LH-20 chromatography with acetone SilFca gel 60 column chromatography with chloroform-methanol (5:l) HPLC (UBondapak CI8, acetonitrile-1% acetic acid (68:32) ) APD-I, I1 and 111 3.1.4

Terferol 141) Structure:

0

\ CH3

Active against: CAMP phosphodiesterase, cGMP phosphodiesterase Producing organism: Streptomyces showdoensis SANK65080

142)

509 3.1.5

Griseolic acid 143)

Structure:

HOOC H

Active against:

CAMP phosphodiesterase 144) Streptomyces griseoaurantiacus SANK63479

Producing organism: 3.2

3.2.1

Inhibitors of Phospholipases N,N'-Ethylenediaminedisuccinic Active against:

phospholipase C, phospholipase D an actinomycetes (MG417-CF17)

Producing organism: 3.2.2

Acid 145)

Plastatin, Luteosporin

146)

Structure: 0

Plastatin:

X=NH2

Luteosporin:

X=OH

Active against:

phospholipase A2

Producing organism:

Penicillium chermesinum (SC 12,932)

510

3.2.3

Plipastatin 147) Structure: L D L D-allo L R-Glu-Orn-Tyr-T hr-Clu-[

L

L

D L yr-I le

X I -Pro-Cln-T

-0 Pli pastati n

A1

R CH3(CH2) 12FHCH2CO-

3 ( R)-hydroxyhexadecanoic

[XI

acid

D -Ala

OH

A2

CH3CH CH(CH2IlO!HCH2CO21 CH3 OH

14(S)-methyl-3(R)-hydroxy-

B1

CH3(CH2) 12YHCH2CO-

3( R ) - hyd roxy hexadecanoic

D-Ala

hexadecanoic acid

acid

D-Val

OH B2

CH CH C H (C H2) OyHCH2CO3 21 CH3 OH

14(S )-methyl-3( R ) -hydroxy-

hexadecanolc acid

Active against: phospholipase A2, C and D

D-Val

148)

Producing organism: Bacillus cereus BMG302-fF67 Isolation: Culture filtrate Amberlite XAD-7 adsorption and elution with 80% methanol Silica gel column adsorption and elution with 80% propanol silanized Silica gel column chromatography with MeOH-acetate buffer Sephadex LH-20 chromatography with 80% MeOH HPLC (Nucleosil 5CI8, acetonitrile-acetate buffer)

2 A2 fraction

Plipastatin A1 fraction

The Amberlite XAD-7 column of the first step was eluted with 90% methanol and further treated in the same way to give B1 and B2 fractions.

These frac-

tions were treated with Sephadex LH-20 and 80% methanol to give pure plipastatin Al, A2, B1 and B2. 3.3

3.3.1

Inhibitor of Alkaline Phosphatase Forphenicine Structure:

149)

150)

Active against: alkaline phosphatase Producing organism:

Actinomyces fulvoviridis var. acarbodicus

511

1

Isolation: Culture filtrate carbon chromatography with 50% ethanol DEAE-Sephadex C-25 chromatography with water recrystallization from water

Pale yellow crystal, forphenicine Forphenicinol, in which the aldehyde group of forphenicine is reduced to carbinol, was revealed to be effective in restoring the immunological parameters and is under clinical investigations in the fields of chronic respiratory 151,152) infections, atypical mycobacteriosis and melanoma. 3.4 3.4.1

Inhibitors of Esterase Esterastin 153) Structure: (S)

(2) (2) CH,(CH,),CH=CHCH,CH=CHCH

(S)

(SI (5)

0 0 I 0 co I CHNHCOCH3 I CH2CONHZ

Active against: pancreatic esterase154) Producing organism: Streptomyces lavendulae MD4-C1 3.4.2

Ebelactone 155) Structure: y 3 y43 y 3 R-CH-CH-CH-CH2-C=CH-CHI I o=c-0

Ebelactone A : Ebelactone B: Active against:

y 3

y 3

R=CH3 R=CH3CH2

156) liver and pancreatic esterase. fMet aminopeptidase

Producing organism: Streptomyces aburaviensis MG7-G1 Isolation: Whole broth butyl acetate extraction Silica gel chromatography with n-hexanechloroform-ethyl acetate reverse phase chromatography with silica gel and 50% methanol

4

Ebelactone A

.)

Ebelactone B

512 3.5

Inhibitor of Ribonuclease

NMP Inhibitor 157)

3.5.1

Structure:

a glycopeptide (2,500 dalton) containing phosphorus

Active against:

Monascus nuclease MP, nuclease P1, venom phosphdiesterase Monascus purpureus Went 908

Producing organism: 3.6

Inhibitor of Adenosylhomocysteine Hydrolase

3.6.1

Neplanocin A Structure: 158)

HOH2C H O OH Active against:

adenosylhomocysteine hydrolase

Producing organism: 3.7

159)

Ampullariella regularis A11079

160)

Inhibitors of Adenosine Deaminase

3.7.1

Coformycin, Deoxycoformycin 16I ,162)

Structure:

OH

OH R

Coformycin : R=OH Deoxymformycin : R-H 2'-Chloropentostatin: R=Cl (adechlorin) Active against:

adenosine deamlnase

Producing organism: 55716'), 3.7.2

g.

antibioticus

163)

Nocardia interforma, Streptomyces kaniharaensis SF162)

2'-Chloropentostatin Structure:

(Adechlorin) written in 3.7.1 164)

Active against:

adenosine deaminase 165,166)

Producing organism:

Actinomadura sp. 0MR-37165),

4. sp.

ATCC39365 166)

513

3.7.3

Adecypenol

167)

Structure: OH

Active against: adenosine deaminase Producing organism: Streptomyces sp. OM-3223 Isolation: Culture filtrate carbon adsorption and elution with aq. acetone Diaion HP-20 chromatography with aq. methanol Toyopearl Hkr-40 chromatography with aq. ethanol reversed phase Silica gel (ODS) chromatography with aq. methanol Adecypenol 3.8 3.8.1

Inhibitors of Adenosine Triphosphatase Coriolin Structure:

168)

Active against:

+ +

(Na ,K )-ATPase

169)

Producing organism: Coriolus consors

170)

Diketocoriolin B, a derivative of 1-octanoylcorio in (coriolin B) is

+ +

I

times stronger in the inhibition of (Na ,K )-ATPase, a membrane bound enzyme, and increased the number of mouse spleen cells producing antibody to sheep 171)

red blood cells. 3.8.2

MF722-02'72) Structure: C29H32N2Y7 Active against:

+

(Na ,K )-ATPase

Producing organism:

Streptomyces pseudovenezuelae MF722-02

514

3.8.3

L-681,110

173)

Structure:

? I

H 3@C 0 -

:

H

CH 3

3

3c H3C HO

CH3 Al:

R=H

A2:

R=OCH3

B1:

R = H and substitution o f OCH3 for fumarate moiety

+ +

Active against: (Na ,K )-ATPase Producing organism: Streptomyces

4. INHIBITORS OF OXIDO-REDUCTASES 4.1 Inhibitors of Tyrosine Hydroxylase

4.1.1 Aquayamycin

174) Structure:

HO

OH

175) Active against: tyrosine hydroxylase, dopamine B-hydroxylase Producing organism: Streptomyces misawaensis nov. s p . HAMADA 4.1.2

176) OKAMI

177)

Chrothiomycin

Structure: C27H31-33013NS with 5-hydroxy-1,4-naphthoquinone moiety Active against: tyrosine hydroxylase, dopamine 8-hydroxylase Producing organism: Streptomyces pluricolorescens

515 4.1.3

Deoxyfrenolicin

178)

Structure: H2-CHj

~

CH2COOH

Active against:

tyrosine hydroxylase

Producing organism: 4.1.4

Oudenone Structure:

179)

Active against:

tyrosine hydroxylase'*'),

Producing organism: 4.2 4.2.1

phenylalanine hydroxylase 180) Oudemansiella radicata

Inhibitors of Dopamine B-hydroxylase Fusaric Acid Structure:

5-butylpicolinic acid

Active against:

dopamine 6-hydroxylase

Producing organism: 4.2.2

Streptomyces fradiae

Fusarium oxysporum

182) 183)

Oosponol Structure:

184)

CH~OH

Active against:

dopamine 6-hydroxylase

Producing organism:

185)

Gloeophyllum striatum, Oospora s p .

181)

516

4.2.3

Dopastin Structure:

186)

61

(CH) ,),CHCHCH,NHCOCH=CHCH, +OH

k0

Active against:

dopamine 6-hydroxylase

Producing organism: 4.3 4.3.1

Structure:

3,4-dihydroxystyrene pteridine-dependent monooxygenases (Phe-, Tyr-, Trp-

Producing organism:

4.4.1

Pseudomonas No. BAC-125

Inhibitor of Phenylalanine Hydroxylase 188) 3,4-Dihydroxystyrene

Active against: hydroxylases)

4.4

187)

Fomes

tasmanicus

Inhibitor of Tryptophan Hydroxylase 2,5-Dihydro-L-phenylalanine 189) Structure:

2,5-dihydro-L-phenylalanine

Active against:

tryptophan hydroxylase

Producing organism:

Streptomyces luteogriseus ME238-AG4

4.5

Inhibitor of Proline Hydroxylase

4.5.1

P-1894B (Vineomycin Al) Structure: 190)

Me Me&o0

Active against:

proline hydroxylase 191)

Producing organism:

Streptomyces albogriseolus subsp. No. 1894

517 4.6

Inhibitor of Monoamine Oxidase 4.6.1 Pimprinine192) Structure: 5,3'-indolyl-2-methyloxazole

H

Active against: monoamine oxidase Producing organism: Actinomycetes MD211-C4 4.7 Inhibitors of Hydroxymethylglutaryl-CoA Reductase 4.7.1 ML-236A, B (Compactin), C, 4a,5-Dihydrocompactin Structure:193,194,196)

ML-236A:

R=OH

ML-2366:

R=OCOCH (CHJ) CH2CH3

ML-236C:

R=H

195) Active against: HMG-CoA reductase Producing organism: Penicillium citrinum SANI;18767193), 194)

2. brevicom-

pactum

193) Isolation: Culture filtrate ethyl acetate extraction at pH 4 Silica gel chromatography with n-hexane-acetone ML-236C-fraction B-fraction

(0:100) A-fraction

(a) Silica gel chromatography with dichloromethane-ethyl acetate (b) Crystallization from benzene (c) Recrystallization with ethanol (d) Distribution between ethyl acetate and water ( e ) Silica gel chromatography with benzene-ethyl acetate

518

CS-514 (6B-hydroxy-ML-236B), which is a biooxidation product of ML-23611 by Mucor hiemalis SANK36372,lg7) is under clinical investigation for hyper198,199) cholesteremia. 4.7.2

Monacolin K (Mevinolin), 4a,5-Dihydromevinolin, Monacolin J, L, X, 4a.5-Dihydromonacolin L, Monacolin M 200-205) Structure:

J:

R=OH

L:

R=H

X:

R=O

+I&

Active against: HMG-CoA reductase Producing organism: Monascus ruber, Aspergillus terreus 4.8 4.8.1

Inhibitor of Aldose Reductase 206) WF 3681 Structure:

Active against:

aldose reductase

Producing organism: Chaetomella raphigera Swift No. 3681

4.9 Inhibitor of 12-Lipoxygenase 4.9.1

3-Methoxytropolone207)

Structure:

Active against: 12-lipoxygenase Producing organism: Streptoverticillium hadanonense KY11449

519

4.10

Inhibitors of Prostaglandin Synthetases 4.10.1 Xanthocillin X Monomethyl Ether208) Structure:

- + + Active against: PG endoperoxide synthase Producing organism: Dichotomomyces cejpii 4.10.2

Thielavin A, B 2 0 9 )

Structure:

A: B:

R1=R2=CH3x3,OCH3xl R1=RZ=CH3x3,OHxl

Active against: PG endoperoxide synthase, PG E2 synthase Producing organism: Thielavia terricola SANK15876

INHIBITORS OF TRANSFERASES 5.1 Inhibitor of Nonspecific N-Methyltranferase 5.1.1 1-[2-(3,4,5,6-Tetrahydropyridyl)]-1,3-pentadiene Structure:

5

H

2 10)

H

Active against: N-methyltransferase Producing organism: Actinomyces strain MD736-C6 5.2

5.2.1

Inhibitors of catechol 0-Methyltransferase 211) Methylspinazarin, 6,7-Dihydrmethylspinazarin Structure:

OH

520

Active against:

COMT, dopamine 6-hydroxylase

Producing organism: 5.2.2

Streptomyces filipinensis MD157-A9

7-0-Methylspinochrome B, 6-(3-hydroxy-n-buty1)-7-0-Methylspinochrome

-p)

Structure:

Active against:

COMT

Producing organism: 5.2.3

213)

Isoflavones Structure:

I: II:

111:

I, 11, I11

R1 O Rl R2 OH OCH3 OH H H OCH3

Active against:

R3

R4 H

OH OCH)

OCH3

OH

OH

COMT, dopa decarboxylase (I, 11)

Producing organism:

5.2.4

Corynespora cassi cola

Streptomyces roseolus ISP5174

Dehydrodicaffeic Acid Dilactone

214)

Structure: HO

OH

OH

(-)-isomer Active against:

COMT, dopa decarboxylase

Producing organism:

Inonotus ep. K-1410

5.3

Inhibitors of Thymidylate Synthetase

5.3.1

Vanoxonin 215) Structure: OH COOH

O i!l,,@ ,,? ~ )

Ac H

H

0 H3C O H 216) Active against: thymldylate synthetase

Producing organism:

Saccharopolyspora hirusta MG245-CF2

5.3.2 Diazaquinomycin 217) Structure:

0

218) Active against: thymidylate synthetase

21 9 ) Producing organism: Streptomyces sp. OM-704 5.4

Inhibitor of Glucosyltransferase (Dextransucrase)

5.4.1

Ribocitrin 220) Structure: COOH CH 1 2 .O-CeCOO H

Hd OH 221) Active against: dextransucrase Producing organism: Streptomyces sp. MF980-CFI Isolation: Culture filtrate Diaion PA316 chromatography with ammonium bicarbonate Sephadex 6-15 chromatography with water DEAE-Sephadex A-25 chromatography with a linear gradient of ammonium bicarbonate (0.05-1.4 M) Silk AR CC-7 chromatography with n-propanol-ammonia Sephadex G-15 chromatography with water White amorphous, rlbocitrin

522

5.5 5.5.1

Inhibitor of Aspartate Aminotransferase 222) Gostatin Structure:

Active against:

aspartate aminotransferase Streptomyces sumanensis nov. sp. NK-23

Producing organism:

Inhibitor of Ornithine-ketoglutarate Aminotransferase 223) 5.6.1 Gabaculine 5.6

Structure:

5-amino-l,3-cyclohexandienyl carboxylate

Active against:

ornithine-ketoglutarate aminotransferase

Producing organism:

Streptomyces toyakaensis

5.7

Inhibitor of Glutamine Amidotransferase

5.7.1

Acivicin (AT-125, U 42,126) 224) Structure:

COOH

Active against:

glutarnine a m i d ~ t r a n s f e r a s e ~ ~ ~aspartate ), synthetase

Producing organism: Streptomyces sviceus 5.8

Inhibitor of Tyrosine Protein Kinase

5.8.1

Erbstatin 226) Structure:

H

F OH H N i = O

Active against:

tyrosine protein kinase

Producing organism:

227)

Streptomyces viridosporus MH435-hF3

523

1

Isolation: Culture filtrate butyl acetate extraction Silica g e l chromatography with chloroform-methanol crystallized from chloroform-nethanol

Erbstatin 5.9

5.9.1

Inhibitors of Reverse Transcriptase 228) Retrostatin Structure: a red indicator acid with quinone group and lacks nitrogen Active against: reverse transcriptase Producing organism:

5.9.2

Streptomyces retrostaticus

Limocrocin

229)

Structure:

230) Active against: reverse transcriptase

Producing organism: Streptomyces limosus 5.9.3

Sakyomicin A-D 231) Structure:

R'

R2

OH

B:

H

D:

H

I

OH

OH

232) Active against: reverse transcriptase

Producing organism: Nocardia M-53

233)

524

5.10 5.10.1

Inhibitor of Aminoglycoside 2"-O-Adenyltransferase 234) 7-Hydroxytropolone

Structure:

Active against : aminoglycoside 2"-O-adenyltransferase Producing organism:

Streptomyces neyagawaensis

6 INHIBITORS OF LYASE 6.1 Inhibitor of Glutamate Decarboxylase 235) 4,5-Dihydroxyisophthalic Acid

6.1.1

Structure:

COOH

H

HO $COO

Active against: glutamate decarboxylase Producing organism: 6.2 6.2.1

Streptomyces toyocaensis no. 1039

Inhibitor of Histidine Decarboxylase Lecanoric Acid 236) Structure:

'0 H

OH

Active against: histidine decarboxylase Proudicng organism: a strain of Pyricularia

6.3 Inhibitor of Dopa Decarboxylase 6.3.1 Isoflavones Structure:237)

OH 0

psi-Tectorigenin : Cenistein New isoflavone : Orobol 8-Hydroxygenistein:

R,=OCH3, RZ= H R ,R = H 1

2

R,=OCH3, R2=OH R , = H , RI=OH R 1=OH, R 2 = H

525

Active against: dopa decarb~xylase~~~), tyrosine protein kinase ( o r o b o l ) 5.8.1 ref. 227. Producing organism: Aspergillus niger NRRL-3122 6.4 Inhibitor of Fumarase 6.4.1 S-2,3-Dicarboxyaziridine 239) Structure:

7""

COO H

240) Active against: fumarase

Producing organism: Streptomyces MD398-A1 6.5

Inhibitors of Glyoxalase I

6.5.1

Glyo-I1 241) Structure:

H I

OH

Active against: glyoxalase I, alkaline phosphodiesterase242,243)

242) Producing organism: Streptomyces griseosporeus NIIDA and OGASAWARA

1

Isolation: Culture filtrate Amberlite XAD-I1 chromatography with 50% acetone butanol extraction at pH 2 Silica gel chromatography with chloroform-methanol Sephadex LH-20 chromatography with methanol recrystallization from chloroform-methanol

Glyo-I1 6.5.2

MS-3

244) Structure: HO

526

Active against:

glyoxalase I

Producing organism:

Stereum hirusutum (mushroom) 2 4 5 )

7 INHIBITOR OF LYGASE 7.1 7.1.1

Inhibitor of Acetyl CoA Carboxylase Decanyl-1-pentenedioic Acid 2 4 6 )

Structure:

decanyl-1-pentenedioic acid

Active against:

acetyl CoA carboxylase

Producing organism:

Gongronella butreli H3180

527 8.

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