ABSTRACT
In search of new anti-tuberculars compatible with anti-retroviral therapy we re-identified amicetin as a lead compound. Amicetin's binding to the 70S ribosomal subunit of Thermus thermophilus (Tth) has been unambiguously determined by crystallography and reveals it to occupy the peptidyl transferase center P-site of the ribosome. The amicetin binding site overlaps significantly with that of the well-known protein synthesis inhibitor balsticidinâ S. Amicetin, however, is the first compound structurally characterized to bind to the P-site with demonstrated selectivity for the inhibition of prokaryotic translation. The natural product-ribosome structure enabled the synthesis of simplified analogues that retained both potency and selectivity for the inhibition of prokaryotic translation.
Subject(s)
Antitubercular Agents/chemistry , Drug Design , Peptides/chemistry , Pyrans/chemistry , Animals , Antitubercular Agents/pharmacology , Chlorocebus aethiops , Crystallography, X-Ray , Humans , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Pyrimidine Nucleosides/chemistry , THP-1 Cells , Thermus thermophilus/chemistry , Vero CellsABSTRACT
A cascade silver(I)-catalyzed hydroamination/Michael addition sequence has been developed to deliver highly substituted bicyclic guanidines. This transformation gives rise to geometrically and constitutionally stable ene-guanidines and generates a remote stereocenter with moderate to high diastereoselectivity.
Subject(s)
Guanidines/chemical synthesis , Catalysis , Cyclization , Guanidines/chemistry , Molecular Structure , Silver/chemistry , StereoisomerismABSTRACT
A concise synthesis of cytimidine was developed utilizing tandem Cu-mediated N-aryl amidations followed by global deprotection. This sequence exploits a regioselective coupling of an iodobenzamide with a halopyrimidine that allows the union of three fragments in a single synthetic manipulation and will permit the efficient and rapid diversification of the cytimidine core.
