ABSTRACT
Tubulysins are cytotoxic natural products with promising anti-cancer properties, originally isolated from myxobacterial cultures. Structurally, tubulysins are tetrapeptides, incorporating three unusual (Mep, Tuv and Tup) and one proteinogenic amino acid (Ile). Here we describe the synthesis and structure-activity relationship studies of novel tubulysin U and V analogues, with variations in the central Tuv fragment, which is known to be of paramount importance for tubulysins' potency and hence cytotoxicity, but has seldom been modified in previous studies. Specifically, we replaced the natural iso-propyl and acetoxy functionalities with other structurally related groups. In general, the new analogues showed much lower potency relative to native tubulysin U. However, one of the synthetic analogues (1f) having a MOM function replacing the acetyl group exhibited a 22 nM IC50 on the HT-29 cell line which is comparable to the IC(50) displayed by tubulysin U (3.8 nM). Furthermore, the synthetic methodology reported herein was found to be flexible enough to deliver different core-modified tubulysin analogues and hence may be regarded as a scalable and convenient strategy for the chemical generation of novel tubulysin analogues.
Subject(s)
Oligopeptides/chemistry , Peptide Fragments , Pipecolic Acids/chemistry , Cell Line, Tumor , Crystallography, X-Ray , Genetic Variation , HT29 Cells , Humans , Inhibitory Concentration 50 , Molecular Structure , Neoplasms/drug therapy , Oligopeptides/chemical synthesis , Oligopeptides/genetics , Peptide Fragments/chemistry , Peptide Fragments/genetics , Peptide Fragments/pharmacology , Pipecolic Acids/chemical synthesis , Structure-Activity RelationshipSubject(s)
Barbiturates/chemistry , Matrix Metalloproteinase 9/chemistry , Protease Inhibitors/chemistry , Barbiturates/chemical synthesis , Barbiturates/pharmacology , Inhibitory Concentration 50 , Matrix Metalloproteinase Inhibitors , Molecular Conformation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , StereoisomerismABSTRACT
The synthesis of a new peptidomimetic structure, the alkene dipeptidosulfonamide isostere, is described. The synthesis is based on a cross metathesis reaction between two allylic building blocks, both in solution and on the solid phase. This method was also applicable to the solid phase synthesis of alkene dipeptide isosteres. Derivatives of amylin(20-29) containing the alkene dipeptidosulfonamide isostere as well as the alkene dipeptide isostere were successfully synthesized using the solid phase cross metathesis method. Investigation of relations between structure and fibril formation of these amylin(20-29) derivatives showed retardation of fibril formation and altered secondary structures, compared to native amylin(20-29).
