Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications.

Auristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates (ADCs). The design and synthesis of several new auristatin analogues with N-terminal modifications that include amino acids with α,α-disubstituted carbon atoms are described, including the discovery of our lead auristatin, PF-06380101. This modification of the peptide structure is unprecedented and led to analogues with excellent potencies in tumor cell proliferation assays and differential ADME properties when compared to other synthetic auristatin analogues that are used in the preparation of ADCs. In addition, auristatin cocrystal structures with tubulin are being presented that allow for the detailed examination of their binding modes. A surprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevant tubulin bound state, whereas in solution this bond is exclusively in the trans-configuration. This remarkable observation shines light onto the preferred binding mode of auristatins and serves as a valuable tool for structure-based drug design.

Pre-fractionated microbial samples--the second generation natural products library at Wyeth.

From the beginning of the antibiotic era in the 1940s to the present, Wyeth has sustained an active research program in the area of natural products discovery. This program has continually evolved through the years in order to best align with the "current" drug discovery paradigm in the pharmaceutical industry. The introduction of high-throughput screening and the miniaturization of assays have created a need to optimize natural product samples to better suit these new technologies. Furthermore, natural product programs are faced with an ever shortening time period from hit detection to lead characterization. To address these issues, Wyeth has created a pre-fractionated natural products library using reversed-phase HPLC to complement their existing library of crude extracts. The details of the pre-fractionated library and a cost-benefit analysis will be presented in this review.

Structure and absolute stereochemistry of 21-hydroxyoligomycin A.

21-Hydroxyoligomycin A (1) was isolated from Streptomyces cyaneogriseus ssp. noncyanogenus (LL-F28249) and fully characterized by NMR and single-crystal X-ray diffraction methods. The complete 1H and 13C NMR chemical shift assignments for 1 were made using 2D NMR experiments, and the chirality at C-21 was deduced to be R from a J-based configuration analysis. The absolute configuration at C-21 and at the other 18 chiral centers in the molecule were independently confirmed by anomalous dispersion measurements on a crystal of the chloroform methanol solvate of 21-hydroxyoligomycin A (1).

Cicadapeptins I and II: new Aib-containing peptides from the entomopathogenic fungus Cordyceps heteropoda.

Fermentation extracts of Cordyceps heteropoda (ARSEF #1880), an entomopathogenic fungus isolated from an Australian cicada, yielded a known antifungal compound, myriocin, and a complex microheterogeneous family of novel nonribosomal peptides, each containing two residues of alpha-aminoisobutyric acid (Aib). Structure elucidation of two major components of the peptide mixture, cicadapeptins I and II (1 and 2), was accomplished by amino acid analysis and various MS, 1-D NMR, and 2-D NMR experiments. Both compounds are acylated at the N-terminus by n-decanoic acid and amidated at the C-terminus by 1,2-diamino-4-methylpentane. The amino acid sequence of cicadapeptin I is N-terminus-Hyp-Hyp-Val-Aib-Gln-Aib-Leu-C-terminus. Ile substitutes for Leu in cicadapeptin II. To our knowledge, this is the first report from fungi of consecutive Hyp or Pro residues in a nonribosomal linear peptide. ROESY data indicated that the cicadapeptins adopt a helical conformation. Cicadapeptins I and II displayed antibacterial activity and limited antifungal activity.

Akanthomycin, a new antibiotic pyridone from the entomopathogenic fungus Akanthomyces gracilis.

[structure: see text] Organic extracts of the entomopathogenic fungus Akanthomyces gracilis ARS 2910 contained antibiotics active against Staphylococcus aureus. Bioassay-guided fractionation of the CH2Cl2 extract yielded the antibacterial compound akanthomycin as a mixture of atropisomers along with the closely related compounds 8-methylpyridoxatin and cordypyridone C. Akanthomycin was characterized using X-ray crystallography and NMR.