Characterization of biologically inactive spirolides E and F: Identification of the spirolide pharmacophore

Tetrahedron Letters

Volumn 37, Issue 43, 1996, Pages 7671-7674

  Hu, Tingmo ^a   Curtis, Jonathan M ^a   Walter, John A ^a   Wright, Jeffrey L C ^a  

^a NATIONAL RESEARCH COUNCIL CANADA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

MARINE TOXIN; SPIROLIDE B; SPIROLIDE E; SPIROLIDE F; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG ISOLATION; DRUG STRUCTURE; DRUG TOXICITY; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; MOUSE; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; SHELLFISH;

ANIMALIA;

EID: 0030597032     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4039(96)01721-2     Document Type: Article

References (14)

1. 1. Hu, T.; Curtis, J.M.; Oshima, Y., Quilliam, M. A., Walter, J.A.; Watson-Wright, W., Wright, J.L.C., J. Chem. Soc., Chem. Commun. 1995, 2159.
2. 2. Uemura, D., Chou, T., Haino, T., Nagatsu, A., Fukuzawa, S., Zheng, S., Chen, H. J. Amer. Chem. Soc. 1995, 117, 1155
3. 3. Seki, T., Satake, M., MacKenzie, L., Kaspar, H. F., Yasumoto, T. Tetrahedron Lett. 1995, 36, 7093
4. 2,3 derivatives of spirolides B and D. Pure spirolide B, subjected to the same HPLC treatment, showed no trace of conversion to spirolide F, confirming the latter is not an artifact of purification. LCMS showed both cyclic imine and keto-amine forms of spirolide were present in the initial methanol shellfish extract.
5. 2 in 2-ethylhexylamine (Sadtler NMR Spectra: δH 2.61 and δC 45.0) are consistent with those of H33 (δ 2.73, 2.86) and C33 (δ 46.6) in 4.
6. 1H NMR data.
7. 13C NMR.
8. 2. The total extract was purified by semi-preparative HPLC (same conditions as in 4 above), yielding ca. 100 μg of pure reduced compound, which was identified as dihydrospirolide B (5) by HRMS and 1D and 2D NMR data (Table 1).
9. 1-labeled 5 was 1Da higher. This, together with the knowledge that reduction took place solely at the imine group, indicates that the deuterium atom is located at C-28.
10. 10. Each spirolide (5 μg) was dissolved in 1% Tween 80 (1.0 ml) and injected i.p. into mice. Death occurred within seven minutes after injection of spirolides A-D. In the case of 3 and 4, both 5 μg and 20 μg doses failed to induce any symptoms.
11. 11. Molecular models were constructed using Hyperchem®, (Hypercube Inc., 419 Phillip St., Waterloo, Ontario, Canada, N2L 3X2) minimized using the MM+ force field to a gradient of 0.1 kcal/(A mol).
12. 12. Falk, M., Spierenburg, P.F., and Walter, J.A., J. Comp. Chem. 1996, 17, 409.
13. 13. Torigoe, K., Murata, M., Yasumoto, T., and Iwashita, T., J. Amer. Chem. Soc. 1988, 110, 7876.
14. 14. Hu, T., deFreitas, A. S. W., Curtis, J. M., Oshima, Y., Walter, J. A., and Wright, J. L. C., J. Nat. Prods. 1996 (in press).