ABSTRACT
A facile, efficient, and highly diastereo- and enantioselective bromoetherification of diolefinic diols has been developed using an amino-thiocarbamate catalyst. Further manipulations of the bromoether products enabled entry into a new class of spirocycles which are distinctively lacking in the literature.
ABSTRACT
The development and use of vaccines and their ability to prevent infection/disease is a shining example of the benefit of biomedical research. Modern vaccines often utilize subunit immunogens that exhibit minimal immunogenicity and require the use of adjuvants to maximize the induction of protective immune responses. We recently described a novel class of vaccine adjuvants, mast cell (MC) activators, that exhibit safe and effective vaccine adjuvant activity when administered by intranasal or intradermal routes. A compound library containing 580 functionalized benzopyrans, a structural motif found in a diverse array of natural and designed bioactive compounds, was screened using a MC degranulation assay to identify novel MC activating compounds for future evaluation as novel vaccine adjuvants. This approach identified 12 novel MC degranulating compounds. Therefore, MC degranulation can be used to reliably detect novel compounds for evaluation as adjuvants for use in mucosal vaccine strategies.
ABSTRACT
Most thiopeptide antibiotics target the translational machinery: thiostrepton (ThS) and nosiheptide (NoS) target the ribosome and inhibit translation factor function, whereas GE2270A/T binds to the elongation factor EF-Tu and prevents ternary complex formation. We have used several in vitro translational machinery assays to screen a library of thiopeptide antibiotic precursor compounds and identified four families of precursor compounds that are either themselves inhibitory or are able to relieve the inhibitory effects of ThS, NoS, or GE2270T. Some of these precursors represent distinct compounds with respect to their ability to bind to ribosomes. The results not only provide insight into the mechanism of action of thiopeptide compounds but also demonstrate the potential of such assays for identifying lead compounds that might be missed using conventional inhibitory screening protocols.
Subject(s)
Anti-Bacterial Agents/chemistry , Prodrugs/chemistry , Ribosomes/metabolism , Anti-Bacterial Agents/pharmacology , Binding Sites , GTP Phosphohydrolases/metabolism , Peptide Elongation Factor Tu/chemistry , Peptide Elongation Factor Tu/metabolism , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Prodrugs/pharmacology , Protein Biosynthesis/drug effects , Ribosomes/chemistry , Thiazoles/chemistry , Thiazoles/pharmacology , Thiostrepton/chemistry , Thiostrepton/pharmacologyABSTRACT
Molecular design and chemical synthesis of several palmerolide A analogues allowed the first structure activity relationships (SARs) of this newly discovered marine antitumor agent. From several analogues synthesized and tested (ent- 1, 5- 14, 21- 26, 50, 51), compounds 25 (with a phenyl substituent on the side chain) and 51 (lacking the C-7 hydroxyl group) were the most interesting, exhibiting approximately a 10-fold increase in potency and equipotency, respectively, to the natural product. These findings point the way to more focused structure activity relationship studies.
Subject(s)
Amides/chemical synthesis , Macrolides/chemical synthesis , Macrolides/pharmacology , Polyenes/chemical synthesis , Adenosine Triphosphatases/antagonists & inhibitors , Amides/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Polyenes/pharmacology , Structure-Activity RelationshipABSTRACT
The total syntheses of the thiopeptide antibiotics GE2270A (7), GE2270T (8), and GE2270C1 (9) are described. The original synthetic strategies employed utilized the hetero-Diels-Alder reaction to construct the pyridine core of the target molecules and relied on a macrolactamization process to construct the macrocycle. The hetero-Diels-Alder-based strategy finally evolved allows the introduction of all four thiazole units attached to the pyridine ring and a one-pot sequence for macrocyclization and side-chain extension, culminating in highly convergent and expedient syntheses of these molecules as exemplified by a 24-step synthesis of GE2270C1 (9).
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Peptides, Cyclic/chemical synthesis , Sulfhydryl Compounds/chemistry , Thiazoles/chemical synthesis , Acetamides/chemistry , Anti-Bacterial Agents/chemistry , Azoles/chemistry , Hydroxylation , Macrolides/chemistry , Molecular Structure , Peptides, Cyclic/chemistry , Phenylalanine/chemistry , Pyridines/chemistry , Thiazoles/chemistryABSTRACT
[reaction: see text] Readily available arabinose-derived ketones, containing a tunable butane-2,3-diacetal as the steric blocker, displayed increasing enantioselectivity (up to 90% ee) with the size of the acetal alkyl group in catalytic asymmetric epoxidation of trans-disubstituted and trisubstituted alkenes. The stereochemical communication between our ketone catalysts and the alkene substrates is mainly due to steric effect, and electronic effect involving pi-pi interaction between phenyl groups of substrate and of catalyst did not appear to be operative in our system.
