ABSTRACT
Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.
Subject(s)
Antiviral Agents/chemistry , Cyclosporine/chemistry , Hepacivirus/physiology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cyclization , Cyclosporine/chemical synthesis , Cyclosporine/pharmacology , Dipeptides/chemical synthesis , Dipeptides/chemistry , Drug Design , Quinidine/chemistry , Stereoisomerism , Virus Replication/drug effectsABSTRACT
The first synthesis of the biologically active humulene natural product asteriscunolide D has been accomplished in nine steps without the use of protecting groups. The challenging 11-membered ring was forged via a diastereoselective thionium ion initiated cyclization, which constitutes a formal aldol disconnection to form a strained macrocycle. A stereospecific thioether activation-elimination protocol was developed for selective E-olefin formation, thus providing access to the most biologically active asteriscunolide. The absolute stereochemical configuration was established by the Zn-ProPhenol catalyzed enantioselective addition of methyl propiolate to an aliphatic aldehyde to afford a γ-hydroxy propiolate as a handle for butenolide formation via Ru-catalyzed alkene-alkyne coupling.
Subject(s)
Biological Products/chemical synthesis , Lactones/chemical synthesis , Quaternary Ammonium Compounds/chemistry , Sesquiterpenes/chemical synthesis , Asteraceae/chemistry , Biological Products/chemistry , Cyclization , Ions/chemical synthesis , Ions/chemistry , Lactones/chemistry , Quaternary Ammonium Compounds/chemical synthesis , Sesquiterpenes/chemistry , StereoisomerismABSTRACT
The development of a general and practical zinc-catalyzed enantioselective alkyne addition methodology is reported. The commercially available ProPhenol ligand (1) has facilitated the addition of a wide range of zinc alkynylides to aryl, aliphatic, and α,ß-unsaturated aldehydes in high yield and enantioselectivity. New insights into the mechanism of this reaction have resulted in a significant reduction in reagent stoichiometry, enabling the use of precious alkynes and avoiding the use of excess dimethylzinc. The enantioenriched propargylic alcohols from this reaction serve as versatile synthetic intermediates and have enabled efficient syntheses of several complex natural products.
Subject(s)
Alcohols/chemistry , Alcohols/chemical synthesis , Alkynes/chemistry , Propanols/chemistry , Propanols/chemical synthesis , Zinc Compounds/chemistry , Zinc/chemistry , Alkynes/chemical synthesis , Catalysis , Ligands , Molecular Structure , StereoisomerismABSTRACT
Over the past decade, large strides have been achieved in the invention of methods for the direct enantioselective addition of alkynes and metal alkynylide nucleophiles into prochiral aldehydes, ketones, and imines. This review highlights and compares the available methods for these transformations.
ABSTRACT
The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli Δ tolC mutant strain.
Subject(s)
Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/pharmacology , Escherichia coli Proteins/antagonists & inhibitors , Heterocyclic Compounds, 2-Ring/pharmacology , Nucleotidyltransferases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Benzimidazoles/metabolism , Benzimidazoles/pharmacology , Binding Sites , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Escherichia coli/drug effects , Escherichia coli/enzymology , Escherichia coli Proteins/chemistry , Escherichia coli Proteins/metabolism , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/metabolism , Microbial Sensitivity Tests , Molecular Structure , Nucleotidyltransferases/chemistry , Nucleotidyltransferases/metabolism , Protein Binding , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Pyrimidinones/metabolism , Pyrimidinones/pharmacology , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/metabolism , Triazoles/pharmacologyABSTRACT
A catalytic enantioselective total synthesis of adociacetylene B (2) in five steps is reported. The efficiency of this synthesis was enabled by an asymmetric zinc alkynylation catalyzed by the proline-derived ligand (1).
Subject(s)
Alkynes/chemical synthesis , Furans/chemical synthesis , Catalysis , Chromatography, High Pressure Liquid , StereoisomerismABSTRACT
Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cyclophilins/antagonists & inhibitors , Cyclosporins/pharmacology , Organic Anion Transporters/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Chemistry Techniques, Synthetic , Crystallography, X-Ray , Peptidyl-Prolyl Isomerase F , Cyclophilins/chemistry , Cyclophilins/metabolism , Cyclosporine/chemistry , Cyclosporine/pharmacology , Cyclosporins/chemistry , Dogs , Hepacivirus/drug effects , Hepatitis C/drug therapy , Humans , Hydrophobic and Hydrophilic Interactions , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Liver-Specific Organic Anion Transporter 1 , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Rats , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Our recent development of a proline-derived bimetallic catalyst has led to a number of efficient, catalytic, enantioselective transformations. Herein, we report a practical and general alkynylation of aromatic and alpha,beta-unsaturated aldehydes using our zinc catalyst system.