ABSTRACT
A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein-ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK.
ABSTRACT
A five-step synthesis of the natural product angelicoin A using a late stage highly regioselective palladium(0)-catalyzed decarboxylative prenyl migration and aromatization sequence as the key step is reported. The method was extended with geranyl migration in eight-step total syntheses of hericenone J and hericenol A from geraniol.
Subject(s)
Neoprene/chemistry , Phenols/chemistry , Phenols/chemical synthesis , Terpenes/chemistry , Terpenes/chemical synthesis , Acyclic Monoterpenes , Catalysis , Molecular Structure , Palladium/chemistry , StereoisomerismABSTRACT
Five-step total syntheses of angelicoin A and B from 2,2,6-trimethyl-4-dioxinone are reported using late stage biomimetic aromatization reactions via diketo-dioxinones as intermediates. In addition, with angelicoin A, this aromatization was coupled with a palladium-catalyzed decarboxylative prenylation in a one-pot sequence as the key step.
Subject(s)
Biomimetic Materials/chemical synthesis , Coumarins/chemical synthesis , Palladium/chemistry , Catalysis , Molecular Structure , PrenylationABSTRACT
The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Interferons/agonists , Toll-Like Receptor 7/agonists , Aldehyde Oxidase/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Discovery , Drug Evaluation, Preclinical , Hepacivirus/physiology , Hepatitis C/virology , Humans , Injections, Intravenous , Interferon Inducers/chemical synthesis , Interferon Inducers/chemistry , Interferon Inducers/pharmacokinetics , Interferon Inducers/pharmacology , Microsomes, Liver/metabolism , Molecular Targeted Therapy , Molecular Weight , Purines/chemical synthesis , Purines/metabolism , Rats , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.
Subject(s)
Antiviral Agents/chemistry , Hepacivirus/drug effects , Purines/chemistry , RNA Virus Infections/drug therapy , Toll-Like Receptor 7/agonists , Administration, Oral , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/therapeutic use , Drug Design , Mice , Models, Animal , Purines/pharmacokinetics , Purines/therapeutic use , Rats , Structure-Activity Relationship , Toll-Like Receptor 7/metabolismABSTRACT
The total synthesis of aigialomycin D, without the need for phenol protection, was carried out using the C-acylation of a keto-dioxinone dianion, a cascade sequence consisting of ketene generation, alcohol trapping and aromatization, and ring-closing metathesis.
Subject(s)
Macrolides/chemical synthesis , Cyclization , Macrolides/chemistry , Molecular StructureABSTRACT
The synthesis and structure-activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound 36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.
Subject(s)
CD4 Antigens/metabolism , HIV Envelope Protein gp120/antagonists & inhibitors , HIV Fusion Inhibitors/chemistry , Isoquinolines/chemistry , Nicotinic Acids/chemistry , Animals , Cells, Cultured , Drug Design , HIV Envelope Protein gp120/metabolism , HIV Fusion Inhibitors/chemical synthesis , HIV Fusion Inhibitors/pharmacokinetics , HIV-1/drug effects , Half-Life , Humans , Isoquinolines/chemical synthesis , Isoquinolines/pharmacokinetics , Nicotinic Acids/chemical synthesis , Nicotinic Acids/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
The antifungal natural product citrafungin A was synthesized using, as key steps, an asymmetric aldol reaction of a chiral oxazolidinone, diastereoselective alkylation of a chiral 1,3-dioxolan-2-one, semihydrogenation of an enyne, and selective methyl ester deprotection.
