The antimicrobial natural product chuangxinmycin and some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase

Bioorganic and Medicinal Chemistry Letters

Volumn 12, Issue 21, 2002, Pages 3171-3174

  Brown, Murray J ^a   Carter, Paul S ^a   Fenwick, Ashley E ^a   Fosberry, Andrew P ^a   Hamprecht, Dieter W ^a   Hibbs, Martin J ^a   Jarvest, Richard L ^a   Mensah, Lucy ^a   Milner, Peter H ^a   O'Hanlon, Peter J ^a   Pope, Andrew J ^a   Richardson, Christine M ^a   West, Andrew ^a   Witty, David R ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; CHUANGXINMYCIN; LACTONE; TRYPTOPHAN TRANSFER RNA LIGASE; UNCLASSIFIED DRUG;

ACYLATION; ANTIMICROBIAL ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG HYDROLYSIS; DRUG POTENCY; DRUG SYNTHESIS; ENZYME INHIBITION; ENZYME PURIFICATION; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; STEREOCHEMISTRY;

ANTI-BACTERIAL AGENTS; BACTERIA; ENZYME INHIBITORS; HYDROLYSIS; INDICATORS AND REAGENTS; INDOLES; MICROBIAL SENSITIVITY TESTS; STAPHYLOCOCCUS AUREUS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TRYPTOPHAN-TRNA LIGASE;

BACTERIA (MICROORGANISMS);

EID: 0037020732     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)00604-2     Document Type: Article

References (25)

1. Chuangxinmycin Research Group, Institute of Materia Media, Chinese Academy of Medical Sciences Sci. Sin. (Engl. Ed.). 20:1977;106.
2. Liang, H.-T.; Hsu, H.-D.; Chang, C.-P.; Ku, H.-E.; Wang, W.-S. Hua Hsueh Hsueh Pao 1976, 34, 129.
3. Gu Z.-P.; Liang, X.-T. Acta Chim. Sin. 1985, 43, 250.
4. Hsu, H.-C.; Shao, M.-C.; Chang, C.-Y.; Li, K.-P.; Chou, K.-C.; Tang, Y.-C. K'o Hsueh T'ung Pao 1980, 25, 350.
5. Qi T.Q., Liu X., Yand Y.F. Chung-Kuo i Hsueh Ko Hsueh Yuan Hsueh Pao Acta Academiae Medicinae Sinicae. 2:1980;32.
6. Tyrosyl tRNA Synthetase Inhibitor: Stefanska, A. L.; Coates, N. J.; Mensah, L. M.; Pope, A. J.; Ready, S. J.; Warr, S. R. J. Antibiotics 2000, 53, 345. Houge-Frydrych, C. S. V.; Readshaw, S. A.; Bell, D. J. J. Antibiotics 2000, 53, 351.
7. Tyrosyl tRNA Synthetase Inhibitor: Stefanska, A. L.; Coates, N. J.; Mensah, L. M.; Pope, A. J.; Ready, S. J.; Warr, S. R. J. Antibiotics 2000, 53, 345. Houge-Frydrych, C. S. V.; Readshaw, S. A.; Bell, D. J. J. Antibiotics 2000, 53, 351
8. Isoleucyl tRNA Synthetase Inhibitor: Stefanska, A. L.; Cassels, R.; Ready, S. J.; Warr, S. R. J. Antibiotics 2000, 53, 357. Houge-Frydrych, C. S. V.; Gilpin, M. L.; Skett P. W.; Tyler J. W. J. Antibiotics 2000, 53, 364.
9. Isoleucyl tRNA Synthetase Inhibitor: Stefanska, A. L.; Cassels, R.; Ready, S. J.; Warr, S. R. J. Antibiotics 2000, 53, 357. Houge-Frydrych, C. S. V.; Gilpin, M. L.; Skett P. W.; Tyler J. W. J. Antibiotics 2000, 53, 364.
10. Seryl tRNA Synthetase Inhibitor: Stefanska, A. L.; Fulston, M.; Houge-Frydrych, C. S. V.; Jones J. J.; Warr, S. R. J. Antbiotics, 2000, 53, 1346.
11. 19 was overexpressed in E. coli and purified using standard procedures.
12. 9,20 SAR screening was carried at a tryptophan concentration equal to Km and with ATP in excess (2.5 mM).
13. Pope A.J., Moore K.J., McVey M., Mensah L., Benson N., Osborne N., Broom N., Brown M.J.B., O'Hanlon P.J. J. Biol. Chem. 273:1998;31691.
14. Su S., Tu J., Zhang S. Yiyao Gongye. 2:1984;17.
15. Matsumoto K., Watanabe N. Heterocycles. 26:1987;1775.
16. The ratio of cis:trans isomer in samples that were tested for biological activity was as follows: 7 1:1, 8 6:1, 9 2:1, 11 1:1, 12 1.3:1, 13 1.1:1, 20 20:1, 21 20:1.
17. Laber B., Gomis-Ruth F.X., Romao M.J., Huber R. Biochem. J. 288:1992;691.
18. Kato, K.; Ono, M.; Akita, H. Tetrahedron Lett. 1997, 38, 1805.
19. Kato, K.; Ono, M.; Akita, H. Tetrahedron: Asymm. 1997, 8, 2295.
20. Mori K., Iwasawa H. Tetrahedron. 36:1980;87.
21. Manchand P.S., Luk K.-C., Belica P.S., Choudhry S.C., Wei C.C. J. Org. Chem. 53:1988;5507.
22. The lactone 20, has a coupling constant S-C H -C H of 6.2 Hz, significantly larger than normally observed values (around 3 Hz for cis isomers, around 4-4.5 Hz for trans isomers). Since a trans fusion of the lactone would geometrically be highly disfavoured this suggests a close-to-eclipsed conformation of the two hydrogen atoms (Karplus curve). Indeed, modelling 20 and chuangxinmycin shows a reduced dihedral angle (from 52.6 to 34.1°) in the tetracyclic compound. The hydrolysed hydroxy-carboxylate 21 has a normal cis coupling constant of 3.0 Hz.
23. Macarrón R., Mensah L., Cid C., Carranza C., Benson N., Pope A., Diez E. Anal. Biochem. 284:2000;183.
24. Hodgson, J. E.; Lawlor, E. J. Eur. Pat. Appl., EP-785263 (to SmithKline Beecham plc), 1997.
25. Brown P., O'Hanlon P.J., Osborne N., Mensah L., Pope A.J., Richardson C.M., Walker G. Bioorg. Med. Chem. 7:1999;2473.