A Facile Semisynthesis and Evaluation of Garcinoic Acid and Its Analogs for the Inhibition of Human DNA Polymerase β

Abstract

Garcinoic acid has been identified as an inhibitor of DNA polymerase β (pol β). However, no structure-activity relationship (SAR) studies of garcinoic acid as a pol β inhibitor have been conducted, in part due to the lack of an efficient synthetic method for this natural product and its analogs. We developed an efficient semi-synthetic method for garcinoic acid and its analogs by starting from natural product δ-tocotrienol. Our preliminary SAR studies provided a valuable insight into future discovery of garcinoic acid-based pol β inhibitors.

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation

“…Methyl acrylate led to desmethyl analogues of 13d with various side-chain lengths. (35); dimethylamine (36); morpholine (37); piperidine (38); N-methylpiperazine (39)], MeOH, reflux, 5 h, 90% for 35, 90% for 36, 95% for 37, 95% for 38, 92% for 39; (f) see Alsabil et al; 38 (g) ethyl acetoacetate (for 42) or diethyl malonate (for 43), piperidine, EtOH, reflux, 1−3 h, 93% for 42, 90% for 43; (h) ethyl bromobutyrate (for 67) or bromoacetamide (for 69), NaH, THF, 0 °C, 4 h, 70% for 67, 66% for 70; (i) succinic anhydride, Et 3 N, THF, rt., 20 h; (j) LiOH 10%, THF, rt., 3 56 similar to the one recently reported by Gujarathi et al 57 Tosyl ester was used as a protecting group of the phenol function rather than a silylated ether. This choice initially aimed at achieving one final deprotection step of all protecting groups.…”

“…The third aforementioned alkene reagent, 2-methylene-1,3-propanediacetate, helped prepare amplexichromanol analogues. Eventually, 14 , 16 – 18 , 28 , and 29 were synthesized in our group through a cross-metathesis approach similar to the one recently reported by Gujarathi et al Tosyl ester was used as a protecting group of the phenol function rather than a silylated ether. This choice initially aimed at achieving one final deprotection step of all protecting groups.…”

“…1 H NMR (400 MHz, CDCl 3 ) δ H 10.83 (s, 1H), 6.73 (dd, J = 7.3, 5.9 Hz, 1H), 6.68 (s, 1H), 5.17− 5.08 (m, 2H), 3.93 (s, 3H), 3.72 (s, 3H), 2.98 (t, J = 6.9 Hz, 2H), 2.26 (s, 2H), 2.19−2.15 (m, 3H), 2.14−2.03 (m, 6H), 1.97 (d, J = 7.9 Hz, 2H), 1.82 (d, J = 1.2 Hz, 3H), 1.74 (d, J = 6.8 Hz, 2H), 1.64− 1.53 (m, 8H), 1.25 (s, 3H). 13 (2R)-2,8,-Dimethyl-2-[(3E,7E)-4,8,12-trimethyldeca-3,7,11-trien-1-yl]-3,4-dihydro-2H-1-benzopyran-6-yl-4-methylbenzene-1-sulfonate (57). To a solution of 6d (600 mg; 1.51 mmol; 1 equiv) in dichloromethane (33 mL) were added 4-toluenesulfonyl chloride (316.5 mg; 1.66 mmol; 1.1 equiv) and trimethylamine (252.2 μL; 1.81 mmol; 1.2 equiv).…”