Development of Synthetic Methodology to Access Glycerol-3-Phosphate Acyltransferase Inhibitors

Obesity;Heterocycles;Glycerol-3-phosphate acyltransferase;Indole;Chemistry

Outlaw, VictorTownsend, Craig A ;

Johns Hopkins University

关键词: Obesity;    Heterocycles;    Glycerol-3-phosphate acyltransferase;    Indole;    Chemistry;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60271/OUTLAW-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Despite a rising demand for anti-obesity therapeutics, few effective pharmacological options are clinically available that target the synthesis and accumulation of body fat. Moderate inhibition of mammalian glycerol-3-phosphate acyltransferase (GPAT) with 2-(alkanesulfonamido)benzoic acids has recently been described in vitro, accompanied by promising weight loss in vivo. Docking studies with 2-(octanesulfonamido)benzoic acid modeled into the active site of squash GPAT revealed an unoccupied volume lined with hydrophobic residues proximal to C–4 and C–5 of the benzoic acid ring. In an effort to produce more potent GPAT inhibitors, a series of 4- and 5-substituted analogs were designed, synthesized, and evaluated for inhibitory activity. In general, compounds containing hydrophobic substituents at the 4- and 5-positions, such as biphenyl and alkylphenyl hydrocarbons, exhibited an improved inhibitory activity against GPAT in vitro. The most active compound, a p-biphenylketo-substituted analog, demonstrated an IC50 of 8.5 μM and represents the best GPAT inhibitor discovered to date. Conversely, further substitution with polar hydroxyl or fluoro groups led to a 3-fold decrease in activity. These results are consistent with the presence of a hydrophobic pocket and may support the binding model as a potential tool for developing more potent inhibitors. The design and synthesis of indole analogs based on the sulfonamidobenzoic scaffold was also undertaken. Since existing methods for their preparation were insufficient, a flexible and efficient route to substituted 7-amino-5-cyanoindoles from pyrrole-3-carboxaldehydes was developed. The route commences with a one-pot, three-component Wittig reaction of the aldehydes with fumaronitrile and a trialkylphosphine. The predominantly E-alkene product positions the allylic nitrile for facile intramolecular Hoeben-Hoesch reaction in the presence of BF3•OEt2. Syntheses of 2,5- and 3,5-disubstituted 7-aminoindoles are illustrated. Additionally, dianion alkylation of the allylic nitrile is demonstrated to furnish, after cyclization, 5,6-disubstituted 7-aminoindoles.Isosteres of indole, N-fused heteroaromatic bicycles were also desired as inhibitor candidates. An efficient route to these heterocycles, including indolizines, imidazo[1,2-a]pyridines, and imidazo[1,5-a]pyridines from azole aldehydes was developed using a related but mechanistically distinct method. A similar three-component Wittig olefination of the aldehydes was optimized to afford predominantly E-alkenes that, upon in situ treatment with catalytic KOH, undergo rapid cycloaromatization. Substituent control of the 1-, 2-, and 3-positions of the resulting heteroaromatic bicycles is demonstrated. Alternatively, the isolable E-alkene Wittig product from pyrrole-2-carboxaldehyde, under dianionic conditions, undergoes selective alkylation with various electrophiles, followed by in situ annulation to indolizines additionally substituted at the 6-position. These routes allow for the rapid generation of heterocyclic libraries for evaluation of GPAT inhibition.