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Bioorg Med Chem. 2006 Dec 01;14(23):7875-9. doi: 10.1016/j.bmc.2006.07.057.

Synthesis and preliminary biological evaluation of beta-carotene and retinoic acid oxidation products.

Bioorganic & medicinal chemistry

E M Kithsiri Wijeratne, Manping X Liu, Narendra B Kantipudi, Claudia B Brochini, A A Leslie Gunatilaka, Louise M Canfield

Affiliations

  1. Southwest Center for Natural Products Research and Commercialization, Office of Arid Lands Studies, College of Agriculture and Life Sciences, The University of Arizona, Tucson, AZ 85706-6800, USA.

PMID: 16908162 DOI: 10.1016/j.bmc.2006.07.057

Abstract

Synthesis of the beta-carotene oxidation product, 2,3-dihydro-5,8-endoperoxy-beta-apo-carotene-13-one (1) was achieved in six steps starting from beta-ionone. Photo-oxygenation of all trans-retinoic acid (8) and 13-cis-retinoic acid (9) produced a mixture of 5S*,8S*-epidioxy-5,8-dihydroretinoic acid (10) and 13-cis-5S*,8S*-epidioxy-5,8-dihydroretinoic acid (11). Methylation of the crude photo-oxygenation mixture afforded the corresponding methyl esters 12 and 13, respectively, both of which underwent ready aerial oxidation yielding hitherto unknown oxidation products of retinoic acid identified as methyl 5S*,8S*-epidioxy-9,10beta-epoxy-5,8,9,10-tetrahydroretinoate (14) and methyl 13-cis-5S*,8S*-epidioxy-9,10beta-epoxy-5,8,9,10-tetrahydroretinoate (15). Evaluation of 1, all trans-retinoic acid (8), 13-cis-retinoic acid (9), and the photo-oxygenation products 10-15 in a panel of five cancer cell lines showed 1 to be inactive and that 11 is significantly cytotoxic compared with the other retinoic acid analogs suggesting the requirement of the carboxylic acid moiety and the cis-geometry of the 13(14) double bond for cytotoxic activity.

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