Molecular shape analysis and activity of tautomycin, a protein phosphatase inhibitor

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 1, 1996, Pages 3-8

  Sugiyama, Yukiteru ^a   Ohtani, Ikuko I ^a   Isobe, Minora ^a   Takai, Akira ^b   Ubukata, Makoto ^c   Isono, Kiyoshi ^d  

^a NAGOYA UNIVERSITY   (Japan)

^b NAGOYA UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^c TOYAMA PREFECTURAL UNIVERSITY   (Japan)

^d TOKAI UNIVERSITY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ENZYME INHIBITOR; OKADAIC ACID; PHOSPHOPROTEIN PHOSPHATASE; PHOSPHOPROTEIN PHOSPHATASE INHIBITOR; TAUTOMYCIN;

ARTICLE; COMPUTER SIMULATION; CONTROLLED STUDY; DRUG STRUCTURE; ENZYME ACTIVITY; ENZYME INHIBITION; LUMINESCENCE; MASS SPECTROMETRY; MOLECULAR DYNAMICS; NUCLEAR MAGNETIC RESONANCE; STRUCTURE ACTIVITY RELATION;

EID: 0030035016     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(95)00546-6     Document Type: Article

References (17)

1. Cohen, P. Annu. Rev. Biochem. 1989, 58, 453-508. Shenolikar, S.; Nairn, A. C. Adv. Second Messenger Phosphoprotein Res. 1991, 23, 1-121.
2. Cohen, P. Annu. Rev. Biochem. 1989, 58, 453-508. Shenolikar, S.; Nairn, A. C. Adv. Second Messenger Phosphoprotein Res. 1991, 23, 1-121.
3. Takai, A.; Sasaki, K.; Nagai, H.; Mieskes, G.; Isobe, M.; Isono, K.; Yasumoto, T. Biochem. J. 1995, 306, 657-665. References cited therein.
4. For structure of tautomycin, see; (a) Ubukata, M.; Cheng, X.-C.; Isobe, M.; Isono, K. J. Chem. Soc., Perkin Trans. 1 1993, 617-624. For total synthesis, see;
5. (b) Oikawa, H.; Oikawa, M.; Ueno, T.; Ichihara, A. Tetrahedron Lett. 1994, 35, 4809-4812.
6. (c) Ichikawa, Y.; Tsuboi, K.; Jiang, Y.; Naganawa, A.; Isobe, M. Tetrahedron Lett. 1995, 36, 7101-7104.
7. MacKintosh, C.; Klumpp, S. FEBS Lett. 1990, 277, 137-140.
8. Isobe, M.; Sugiyama, Y.; Ito, T.; Ohtani, I.I.; Toya, Y.; Nishigohri, Y.; Takai, A. Biosci. Biotech. Biochem. 1995, 59, 2235-2238. This method is applicable to PP1 as well as PP2A. Preliminary experiments showed that PP1 inhibitory activity of 1 could be detected by our method. Detail assay of 1 and related compounds will be reported elsewhere.
9. The PP inhibitory activity is frequently determined at pH 8.4. [Takai, A.; Mieskes, G. Biochem. J. 1991, 275, 233-239.]
10. We attempted to prepare 9 and 10 to reveal whether hydroxyl group at C3' is required for activity. Since 7 was only obtained by treatment of 1 with alkali (pH 9), we first synthesized 2-4 by coupling of 7 with synthetic 6 or its analogues. The preparation of 9 and 10 is now under investigation. (equation presented)
11. 3 (97% yield) (v) HF·Py/THF (76% yield).
12. Hydrolysis of 5 to 8 was not observed under this condition.
13. Tachibana, K.; Scheuer, P. J.; Tsukitani, Y.; Kikuchi, H.; Van Engen, D.; Clardy, J. J. Am. Chem. Soc. 1961, 103, 2469-2471.
14. Quinn, R. J.; Taylor, C.; Suganuma, M.; Fujiki, H. BioMed. Chem. Lett. 1993, 1029-1034.
15. Molecular mechanics calculations were carried out on a Silicon Graphics Power Iris 220GTXD computer using Biograf and NMRgraf programs version 3.2.1. (Molecular Simulations, Inc.). Dreiding-II was used for force field. [Maya, S. L.; Olafson, B. D.; Goddard III, W. A. J. Phys. Chem. 1990, 94, 8897-8909.] The J values calculated for the most stable conformation by MacroModel version 4 were similar to those observed for corresponding protons. (equation presented)
16. 3.
17. Detail calculation is now under investigation.