ABSTRACT
The use of an interleukin ß antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1ß into active IL-1ß, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.
Subject(s)
Acne Vulgaris/drug therapy , Caspase 1/metabolism , Caspase Inhibitors/administration & dosage , Caspase Inhibitors/pharmacology , Drug Design , Acne Vulgaris/enzymology , Administration, Topical , Animals , Caspase 1/chemistry , Caspase Inhibitors/pharmacokinetics , Caspase Inhibitors/therapeutic use , Cell Line , Humans , Mice , Models, Molecular , Protein Conformation , Solvents/chemistry , Tissue DistributionABSTRACT
Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50â¯=â¯17â¯nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors.
Subject(s)
4-Butyrolactone/analogs & derivatives , Caspase 1/chemistry , Caspase Inhibitors/chemistry , Dipeptides/chemistry , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , 4-Butyrolactone/metabolism , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/metabolism , Binding Sites , Biological Products/chemistry , Biological Products/metabolism , Caspase 1/metabolism , Caspase Inhibitors/metabolism , Crystallography, X-Ray , Dipeptides/chemical synthesis , Dipeptides/metabolism , Hydrogen Bonding , Inhibitory Concentration 50 , Molecular Conformation , Molecular Docking Simulation , Protein Structure, TertiaryABSTRACT
ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.
Subject(s)
ATPases Associated with Diverse Cellular Activities/antagonists & inhibitors , ATPases Associated with Diverse Cellular Activities/metabolism , DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/metabolism , Molecular Probes/chemistry , Molecular Probes/pharmacology , Protein Interaction Maps/drug effects , Protein Multimerization/drug effects , ATPases Associated with Diverse Cellular Activities/chemistry , Cell Line, Tumor , Chromatin/metabolism , DNA-Binding Proteins/chemistry , Drug Discovery , Histones/metabolism , Humans , Ligands , Models, Molecular , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/chemistry , Protein Isoforms/metabolismABSTRACT
The synthesis of an unnatural polyprenylated acylphloroglucinol (PPAP), regioisomeric with nemorosone and clusianone, has been accomplished. The separated enantiomers of this new PPAP, along with those of nemorosone and clusianone, have been screened for activity against HeLa (cervix carcinoma), MIA-PaCa-2 (pancreatic carcinoma), and MCF7 (mamma carcinoma) cancer cell lines. All of the isomers examined gave surprisingly similar results in the screens.
Subject(s)
Antineoplastic Agents/pharmacology , Benzophenones/pharmacology , Bridged Bicyclo Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzophenones/chemical synthesis , Benzophenones/chemistry , Benzoquinones , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , MCF-7 Cells , Molecular Conformation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Bridgehead lithiations have successfully been carried out on substrates derived from catechinic acid, which possess the core bicyclo[3.3.1]nonane-1,3,5-trione structure present in garsubellin A. Using an external quench method, various electrophiles have been incorporated at the C-5 bridgehead position in a one-step process that appears to be sensitive to the substitution pattern on the bicyclic system. Regioselective lithiation at the C-3 sp(2) centre was achieved by changing the base used from LDA to LTMP. Following the introduction of a prenyl substituent by bridgehead substitution, annulation of a THF ring, analogous to that in garsubellin A, was possible via an epoxidation-ring opening sequence. Oxidative modification of the catechol substituent of the catechinic acid core was possible to give systems with muconic acid, ortho-quinone or furan 2-carboxylic acid side chains.
Subject(s)
Biomimetic Materials/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Catechin/analogs & derivatives , Terpenes/chemical synthesis , Biomimetic Materials/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Models, Molecular , Molecular Structure , Oxidation-Reduction , Terpenes/chemistryABSTRACT
The synthesis of polyprenylated phloroglucinol natural products, including clusianone, nemorosone, and garsubellin A, was pursued by a strategy involving construction of a core bicyclo[3.3.1]nonanetrione structure and subsequent elaboration via organolithium intermediates. Appropriate bridged core structures were obtained through the cyclization of a suitably substituted cyclohexanone enol ether or enol silane with malonyl dichloride. Additional substituents were then introduced by means of regioselective lithiation reactions, including the generation of bridgehead enolates, thus enabling the total synthesis of clusianone and also of an advanced intermediate toward nemorosone. In the case of garsubellin A, an additional THF-like ring was elaborated by a biomimetic 5-exo-tet cyclization of an enol ether (or enol) with a side-chain epoxide. This enabled a formal synthesis of racemic garsubellin A by accessing one of the late intermediates in the Danishefsky synthesis.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Neoprene/chemistry , Phloroglucinol/chemistry , Terpenes/chemical synthesis , Acylation , Alkylation , Benzophenones , Benzoquinones , Bridged Bicyclo Compounds/chemistry , Chlorine/chemistry , Copper/chemistry , Cyclization , Ether/chemistry , Molecular Structure , Silanes/chemistry , Stereoisomerism , Terpenes/chemistryABSTRACT
A chiral base kinetic resolution of an advanced bicyclic intermediate enabled access to the polyprenylated phloroglucinol natural product (+)-clusianone in enantiomerically pure form. X-ray structure determination of another product obtained by the same method then allowed the absolute stereochemistry of (+)-clusianone to be assigned.
Subject(s)
Amides/chemistry , Bridged Bicyclo Compounds/chemistry , Lithium/chemistry , Molecular Conformation , Benzophenones , Benzoquinones , Kinetics , Models, Molecular , Molecular StructureABSTRACT
[Structure: see text] A concise synthesis of the polyprenylated acylphloroglucinol natural product, clusianone, in racemic form, is described. An Effenburger cyclization generated a core bicyclo[3.3.1]nonane-trione structure, which was then elaborated by means of regioselective lithiation reactions.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Clusiaceae/metabolism , Benzophenones , Benzoquinones , Bridged Bicyclo Compounds/metabolism , Molecular StructureABSTRACT
[reaction: see text] Enantioselective deprotonation of 4-substituted cyclohexanones and highly stereoselective conjugate addition of higher order mixed cuprates were the key steps in a concise synthesis of fumagalone-related molecules. The origin of the (low) biological activity of the new compounds as compared to fumagalone is briefly discussed.
Subject(s)
Aminopeptidases/antagonists & inhibitors , Cyclohexanones/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Epoxy Compounds/chemical synthesis , Metalloendopeptidases/antagonists & inhibitors , Cyclohexanes , Cyclohexanones/chemistry , Cyclohexanones/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Epoxy Compounds/chemistry , Epoxy Compounds/pharmacology , Fatty Acids, Unsaturated/chemistry , Molecular Conformation , Sesquiterpenes , StereoisomerismABSTRACT
The preparation of a series of new fumagillin-derived MetAP-2 inhibitors is described. The synthetic approach was designed so as to permit modification of the fumagillin backbone at sites inaccessible through semisynthesis or previously existing total syntheses. An Evans aldolization and a ring-closing metathesis allowed the preparation of a pivotal intermediate which could then be functionalized in various ways using already established or newly developed methodologies.
