Pepticinnamins, new farnesyl-protein transferase inhibitors produced by an actinomycete. II. Structural elucidation of pepticinnamin E.

Abstract

Structure of novel farnesyl transferase inhibitor, pepticinnamin E, is elucidated by NMRstudy. Pepticinnamin E is composedof five amino acids and o-pentenylcinnamic acid, having a molecular weight of 907. C-terminal glycylserine of the compounds is in the cyclized diketopiperazine form.Pepticinnamins are novel farnesyl transferase inhibitors isolated from the cultured broth of Streptomyces sp. OH-4652.1* Here, we report on the structural elucidation of pepticinnamin E (1, Fig. 2), a major componentof pepticinnamins.

Synthesis and In Vitro Evaluation of the Ras Farnesyltransferase Inhibitor Pepticinnamin E

“…[9] Pepticinnamin E (1, Scheme 1) is a natural PFT inhibitor from Streptomyces species [10] which could meet these demands. We now report on the synthesis of both diastereomers of this unusual peptidic natural product (the absolute configuration of the central non-proteinogenic amino acid was not known) and on the evaluation of their PFT-inhibiting properties employing a recombinant protein farnesyltransferase.…”

Application of 3D NMR for Structure Determination of Peptide Natural Products

“…Only some analogues of 3-(2-methylphenyl)acrylic acid residue were rarely descried in peptides, such as WS9326s, 33 pepticinnamins, 34 and mohangamides 35 incorporating a 2-pentenyl cinnamic acid moiety, skyllamycins A and B 36,37 incorporating a 2-propenyl]-cinnamic acid moiety, and corprisamides A and B bearing 2-heptatrienyl cinnamic acid moiety. 38 Moreover, another remarkable feature of compound 2 is the high content of the β -hydroxy- α -amino acids, including genetically coded proteinogenic amino acids Ser and Thr, and nonstandard amino residue 3-OH-Leu.…”

Organic Synthesis and Biological Signal Transduction

“…In addition, natural products with potent PFTinhibiting activity were found in screening tests including, for example, zaragozic acids (e.g. 36), [118] manumycin (37), [119] and pepticinnamin E (38) [120] (Scheme 24).…”

“…[120] One can speculate that the natural product is a transition state analogue for farnesyltransferase, in which the hydrophobic alkenyl acrylic acid imitates the prenyl residue and the conformationally rigid N-methylated peptide skeleton imitates the peptide substrate. A total synthesis of the natural product is of considerable interest since the absolute configuration of the unusual central amino acid is unknown.…”