title: Synthesis of apo-13- and apo-15-lycopenoids, cleavage products of lycopene that are retinoic acid antagonists.
abstract: Consumption of the tomato carotenoid, lycopene, has been associated with favorable health benefits. Some of lycopene's biological activity may be due to metabolites resulting from cleavage of the lycopene molecule. Because of their structural similarity to the retinoic acid receptor (RAR) antagonist, β-apo-13-carotenone, the "first half" putative oxidative cleavage products of the symmetrical lycopene have been synthesized. All transformations proceed in moderate to good yield and some with high stereochemical integrity allowing ready access to these otherwise difficult to obtain terpenoids. In particular, the methods described allow ready access to thetransisomers of citral (geranial) and pseudoionone, important flavor and fragrance compounds that are not readily available isomerically pure and are building blocks for many of the longer apolycopenoids. In addition, all of the apo-11, apo-13, and apo-15 lycopenals/lycopenones/lycopenoic acids have been prepared. These compounds have been evaluated for their effect on RAR-induced genes in cultured hepatoma cells and, much like β-apo-13-carotenone, the comparable apo-13-lycopenone and the apo-15-lycopenal behave as RAR antagonists. Furthermore, molecular modeling studies demonstrate that the apo-13-lycopenone efficiently docked into the ligand binding site of RARα. Finally, isothermal titration calorimetry studies reveal that apo-13-lycopenone acts as an antagonist of RAR by inhibiting coactivator recruitment to the receptor.
authors.affiliation: Department of Human Sciences, The Ohio State University, Columbus, OH 43210.|Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210.
authors.forename: Sureshbabu
authors.initials: S
authors.lastname: Narayanasamy
authors.affiliation: Department of Human Sciences, The Ohio State University, Columbus, OH 43210.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Pavlovicz
authors.affiliation: Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210.
authors.forename: Abdulkerim
authors.initials: A
authors.lastname: Eroglu
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210.
authors.forename: Cassandra E
authors.initials: CE
authors.lastname: Rush
authors.affiliation: Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Sunkel
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210.|Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Human Sciences, The Ohio State University, Columbus, OH 43210 Curley.1@osu.edu Harrison.304@osu.edu.|Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210.
authors.forename: Earl H
authors.initials: EH
authors.lastname: Harrison
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210 Curley.1@osu.edu Harrison.304@osu.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Curley
mesh_terms: D002338:Carotenoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D000077276:Lycopene; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D018168:Receptors, Retinoic Acid; D002338:Carotenoids; D000077276:Lycopene
keywords: apolipoprotein-13-lycopenone; apolycopenoids; chemical synthesis; diet and dietary lipids; gene expression; nuclear receptors; retinoic acid receptor antagonist; retinoids/vitamin A