ABSTRACT
The synthesis of a new generation of highly cytotoxic tubulysin analogues (i.e., tubugis) is described. In the key step, the rare, unstable, and synthetically difficult to introduce tertiary amide-N,O-acetal moiety required for high potency in natural tubulysins is replaced by a dipeptoid element formed in an Ugi four-component reaction. Two of the four components required are themselves produced by other multicomponent reactions (MCRs). Thus, the tubugis represent the first examples of the synthesis of natural-product-inspired compounds using three intertwined isonitrile MCRs.
Subject(s)
Antineoplastic Agents/pharmacology , Biological Products/chemistry , Molecular Mimicry , Peptides/pharmacology , Antineoplastic Agents/chemistry , Dose-Response Relationship, Drug , Peptides/chemistryABSTRACT
The first total synthesis of tubulysin B is described. The aziridine route to tubuphenylalanine (Tup) of the tubulysin D/U-series could not be transferred to the synthesis of tubutyrosine (blue moiety). Therefore, tubutyrosine (Tut) was synthesized by a Wittig olefination/diastereoselective catalytic reduction sequence. Interestingly, the C-2 epimer of tubulysin B has a cytotoxic activity almost identical to the natural diastereomer.
Subject(s)
Oligopeptides/chemical synthesis , Pipecolic Acids/chemical synthesis , Tubulin Modulators/chemical synthesis , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Myxococcales/chemistry , Oligopeptides/chemistry , Oligopeptides/pharmacology , Pipecolic Acids/chemistry , Pipecolic Acids/pharmacology , Stereoisomerism , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
Bile acids are important scaffolds in medicinal and supramolecular chemistry. However, the use of seco bile acids, i.e., bile acids with opened rings, as cores or building blocks for the assembly of complex peptide conjugates or macrocycles has remained elusive so far. A biomimetic approach to secocholanes, based on an oxidative ring-expansion/ring-opening sequence, offers efficient access to novel structures with tunable flexibility and functionality. The process preserves selected portions of the original stereochemical and functional information of the steroid, while additional structural elements are incorporated in further (diversity-generating) steps. The potential of these building blocks for peptide and macrocycle chemistry is exemplified by the attachment of relevant alpha-amino acids and by the production of various complex macrocycles obtained by conventional (e.g., macrolactonization and macrolactamization) and multicomponent (e.g., Ugi four-component) macrocyclizations. This combination of secocholanic skeleton manipulation with, e.g., varied types of macrocyclization protocols, produces high levels of skeletal diversity and complexity. Therefore, this approach may have applicability either for the synthesis of biologically active ligands or as artificial receptors ("hosts").
Subject(s)
Bile Acids and Salts/chemistry , Biomimetic Materials/chemistry , Cholanes/chemistry , Macrocyclic Compounds/chemistry , Peptides/chemistry , Biomimetic Materials/chemical synthesis , Lactams, Macrocyclic/chemical synthesis , Lactams, Macrocyclic/chemistry , Macrocyclic Compounds/chemical synthesis , Peptides/chemical synthesisABSTRACT
A detailed study of the Baeyer-Villiger reaction of 3-ketosteroids has been performed by using m-chloroperoxybenzoic and trifluoroperoxyacetic acids as oxidants. The process was fully regiospecific for 3-keto-5alpha-steroids with the employ of both peracids, and only partially regioselective for 3-keto-5beta-steroids by using trifluoroperoxyacetic acid. Interestingly, the reaction resulted completely unselective for 3-keto-5beta-steroids by using m-chloroperoxybenzoic acid. Theoretical studies were performed to explain the regiochemistry of this process, which is suggested to be controlled by conformational effects in the transition state of the Criegee rearrangement.
