Studies directed towards the development of cyclic peptide-based analogs of macrolide immunosuppressants

Pure and Applied Chemistry

Volumn 68, Issue 3, 1996, Pages 565-568

  Chakraborty, Tushar K ^a  

^a INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY   (India)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0003850337     PISSN: 00334545     EISSN: None     Source Type: Journal    
DOI: 10.1351/pac199668030565     Document Type: Article

References (10)

1. a) P.J. Beishaw, S.D. Meyer, D.D. Johnson, D. Romo, Y. Ikeda, M. Andrus, D.G. Albery, L.W. Schultz, J. Clardy and S.L. Schreiber. Syn. Lett. 381 (1994) and references cited therein
2. b) K.K. Maggon. DN & P 7, 389 (1994) and references cited therein.
3. The peptide residue MeLeu-Val-MeLeu-Ala-OBzl (residues 4 to 7 of cyclosporin) was kindly provided by Dr.R.M. Wenger of Sandoz Pharma AG; see also R.M. Wenger. Helv. Chim. Acta. 67, 502 (1994).
4. All new compounds were characterized by spectroscopic methods. Yields refer to spectroscopically and chromatographically homogeneous materials.
5. M.T. Goulet and J. Boger. Tetrahedron Lett. 31, 4845 (1990). The reported procedure was modified slightly: after the ozonolysis step, the product was isolated by chromatography, treated first with DBU in DMF for 4h to ensure complete retro-aldol reaction, followed by treatment with benzyl bromide to get the benzyl ester 5.
6. 2; b) MeLeu-Val-MeLeu-Ala-OBzl (ref.2) was coupled as described above (ref.5a) with suitably protected amino acid and benzyl ester removed by basic hydrolysis.
7. The binding capabilities of the ligands with FKBP12 were measured by a competitive binding assay developed in Sandoz which determined their affinities for FKBP12 compared to that of ascomycin. The IC50 values for ascomycin and rapamycin by the same assay were 0.5 nM and 0.45 nM respectively.
8. Little epimerization could not be avoided. The minor isomers could be separated easily by chromatography after macrocyclization step.
9. G.D. Van Duyne, R.F. Standaert, S.L. Schreiber and J. Clardy. J. Am. Chem. Soc. 113, 7433 (1991).
10. All calculations were carried out using Insight II (2.2.0)/Discover (2.9) program in Silicon Graphics (4D-80) and Alliant concentrix 2800 (2.2.00, Mode FX28).