ABSTRACT
In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.
Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Fatty Acid Elongases/antagonists & inhibitors , Pyrimidines/pharmacology , Administration, Oral , Adrenoleukodystrophy/drug therapy , Animals , Biological Availability , Dogs , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Ethers/chemistry , HEK293 Cells , Humans , Macaca fascicularis , Mice , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , RatsABSTRACT
Accumulation of very long chain fatty acids (VLCFAs) due to defects in ATP binding cassette protein D1 (ABCD1) is thought to underlie the pathologies observed in adrenoleukodystrophy (ALD). Pursuing a substrate reduction approach based on the inhibition of elongation of very long chain fatty acid 1 enzyme (ELOVL1), we explored a series of thiazole amides that evolved into compound 27âa highly potent, central nervous system (CNS)-penetrant compound with favorable in vivo pharmacokinetics. Compound 27 selectively inhibits ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts, lymphocytes, and microglia. In mouse models of ALD, compound 27 treatment reduced C26:0 VLCFA concentrations to near-wild-type levels in blood and up to 65% in the brain, a disease-relevant tissue. Preclinical safety findings in the skin, eye, and CNS precluded progression; the origin and relevance of these findings require further study. ELOVL1 inhibition is an effective approach for normalizing VLCFAs in models of ALD.
Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Fatty Acid Elongases/administration & dosage , Pyrazoles/pharmacology , Adrenoleukodystrophy/drug therapy , Adrenoleukodystrophy/pathology , Amides/chemistry , Animals , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Humans , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Structure-Activity RelationshipABSTRACT
Two new mycolactones, mycolactones S1 and S2, were isolated from culture agar of Mycobacterium ulcerans subsp. shinshuense. Their structures were established in a three-step procedure: (1) probable structures were speculated from MS analysis; (2) candidates were synthesized; (3) HPLC profiles were established for identification of the natural products. Newly isolated mycolactones correspond to the "oxidized forms" of mycolactone A/B, the causative toxin of Buruli ulcer, isolated from Mycobacterium ulcerans.
Subject(s)
Macrolides/chemical synthesis , Mycobacterium ulcerans/chemistry , Buruli Ulcer/etiology , Chromatography, High Pressure Liquid , Macrolides/chemistry , Molecular StructureABSTRACT
A highly efficient, scalable, and stereoselective synthesis of the mycolactone core is reported. The synthesis consists of 14 longest linear steps, with 19% overall yield.
ABSTRACT
A novel mycolactone has been identified from Mycobacterium marinum infecting freshwater fish.
Subject(s)
Bacterial Toxins/chemistry , Mycobacterium marinum/chemistry , Animals , Bacterial Toxins/biosynthesis , Bacterial Toxins/isolation & purification , Fishes , Fresh Water , Macrolides , Molecular Structure , Mycobacterium marinum/metabolism , Seawater , StereoisomerismSubject(s)
Antineoplastic Agents/chemical synthesis , Ethers, Cyclic/chemical synthesis , Furans/chemical synthesis , Ketones/chemical synthesis , Neoplasms/drug therapy , Pyrans/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Ethers, Cyclic/chemistry , Ethers, Cyclic/pharmacology , Furans/chemistry , Furans/pharmacology , Humans , Ketones/chemistry , Ketones/pharmacology , Macrolides , Pyrans/chemistry , Pyrans/pharmacology , Structure-Activity RelationshipABSTRACT
Four corners: The syntheses of four key building blocks for the total synthesis of norhalichondrin B (see structure) are described. The assembly of these subunits into the natural product is also reported. Key features of the synthesis are the use of the Achmatowicz oxidation/ionic hydrogenation for the synthesis of pyrans and pyranopyrans, and the application of tandem metathesis for the synthesis of pyranopyrans.
Subject(s)
Furans/chemical synthesis , Pyrans/chemical synthesis , Furans/chemistry , Hydrogenation , Pyrans/chemistryABSTRACT
A concise route to the C1-C15 domain of the halichondrins is described. The key reaction is the conversion of a furfuryl alcohol to a pyranone. The stereocenter of this pyranone serves as the starting point for the other 8 stereocenters.
ABSTRACT
A synthesis of highly functionalized pyranopyrans based on an Achmatowicz oxidation followed by a remarkably diastereoselective Kishi reduction is described in the context of studies directed toward norhalichondrin B.
