Synthesis and preliminary biological evaluation of beta-carotene and retinoic acid oxidation products.
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.
Kithsiri Wijeratne
E M
EM
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.
Liu
Manping X
MX
Kantipudi
Narendra B
NB
Brochini
Claudia B
CB
Leslie Gunatilaka
A A
AA
Canfield
Louise M
LM
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D045792:Norisoprenoids / Q000737:chemistry; D010084:Oxidation-Reduction; D010777:Photochemistry; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000138:chemical synthesis* / Q000737:chemistry; D019207:beta Carotene / Q000138:chemical synthesis* / Q000737:chemistry
D000970:Antineoplastic Agents; D045792:Norisoprenoids; D019207:beta Carotene; D014212:Tretinoin; C008157:beta-ionone