Cyclosporine chemistry

Price S L, R J Harrison and M F Guest 1989. An Ab Initio Distributed Multipole Study of the Electrostatic Potential Around an Undecapeptide Cyclosporin Derivative and a Comparison with Point Charge Electrostatic Models. Journal of Computational Chemistry 10 552-567. 

Steinmann, B., Bruckner, P. and Superti-Furga, A. (1991) Cyclosporin A slows collagen triple-helix formation in vivo indirect evidence for a physiological role of peptidyl prolyl cis-trans isomer use. Journal ofBiological Chemistry 266,1299-1303. 

M Wenger. The chemistry of cyclosporine, in R Ramage, R Epton, eds. Peptides 1996. Proceedings of the 24th European Peptide Symposium. Mayflower, Kingswoodford, 1998, pp 173-178. 

A second enzyme (of mass 100 kDa) is needed for activation of phenylalanine. It is apparently the activated phenylalanine (which at some point in the process is isomerized from l- to D-phenylalanine) that initiates polymer formation in a manner analogous to that of fatty acid elongation (Fig. 17-12). Initiation occurs when the amino group of the activated phenylalanine (on the second enzyme) attacks the acyl group of the aminoacyl thioester by which the activated proline is held. Next, the freed imino group of proline attacks the activated valine, etc., to form the pentapeptide. Then two pentapeptides are joined and cyclized to give the antibiotic. The sequence is absolutely specific, and it is remarkable that this relatively small enzyme system is able to carry out each step in the proper sequence. Many other peptide antibiotics, such as the bacitracins, tyrocidines,215 and enniatins, are synthesized in a similar way,213 216 217 as are depsipeptides and the immunosuppresant cyclosporin. A virtually identical pattern is observed for formation of polyketides,218 219 whose chemistry is considered in Chapter 21. 

Natural products have been identified as the active principle of herbs and extracts used in folk medicine [1], The importance of natural products in the pharmaceutical industry has continued to the present day and is reflected by the fact that close to half of the best selling pharmaceuticals are either natural products (e.g. cyclosporine, Taxol, FK 506) or derivatives thereof [3]. In high throughput screening processes performed by the pharmaceutical industry natural product extracts exhibit a hit rate which is estimated to be substantially higher than the hit rate of random libraries from combinatorial chemistry. Natural products such as epothilones, discodermolide or ecteinascidin are promising clinical candidates for future cancer treatment. 

Wenger RM. Pharmacology of cyclosporin sandimmune. JJ. Chemistry. Pharmacol. Rev. 1990 41 243-247. 

Schreiher SL. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science 1991 251 283-287. Ho S, Clipstone N, Timmermann L, Northrop J, Graef J, Fiorentino D, Nourse J, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Clin. Immunol. Jmmunopathol. 1996 80 40-45. 

In peptide chemistry, activation with pivalic acid mixed anhydrides allows condensation with a-alkyl-a-amino acids (e.g. Aib), A -methyl-a-amino acids (resulting in the total synthesis of cyclosporin A) and Boc-Asn. ... 

Y. Lavie, H. Cao, A. Volner, et al. Agents that reverse multidrug resistance, tamoxifen, verapamil, and cyclosporin q block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells. Journal of Biological Chemistry 272 1682 (1997). 

Natural products are generally complex chemical structures, whether they are cyclic peptides like cyclosporin A, or complex diterpenes like paclitaxel. Inspection of the structures that are discussed in Section IV is usually enough to convince any skeptic that few of them would have been discovered without application of natural products chemistry. Recognition and appreciation of the value of natural prod-uct-like models in improving efficiency in so-called diver-sify-orienfed synfhesis has already been mentioned. 

The design of selective and potent inhibitors of PPIases is of interest and numerous molecules have been designed or selected from chemical libraries with a view to curing these major diseases. The study of Pinl, which is clearly distinct from other members of the PPIase family on the basis of structure, binding site, catalytic mechanism, and biological implications, has opened up new perspectives in the biological chemistry of PPIases. The recent discoveries of the secondary amide peptide bond cis-trans isomerase (APIase) DnaK [209] and of a novel class of FK506 and cyclosporine-sensitive PPIase [210] are also major advances in this field. 

Mikol, V, Papageorgiou, C., and Borer, X. (1995) The role of water-molecules in the structure-based design of (5-hydroxynorvalme)-2-cyclosporine -synthesis, biological-activity, and crystallographic analysis with cyclophilin-A. Journal of Medicinal Chemistry, 38, 3361-3367. 

The influence of natural products in the discovery of new marketed therapeutics continues to be significant in various therapeutic areas. Burger s Medicinal Chemistry and Drug Discovery reviews natural products as leads for new pharmaceutical products for the central nervous system, neuromuscular disease, cancer, bacterial infections, cardiovascular disease, asthma, and parasites. Dmgs such as morphine, penicillin, cyclosporine A, lovastatin, acarbose, FK506 (tacrolimus), and pachtaxel (Taxol )... 

Lawen A. Biosynthesis and mechanism of action of cyclosporins. Ellis GP, Luscombe DiC, eds. Progress in Medicinal Chemistry, Vol. 33. Amsterdam Elsevier Science Publishers, 1996 53-97. 

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