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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Tretinoin/chemical synthesis , beta Carotene/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , Norisoprenoids/chemistry , Oxidation-Reduction , Photochemistry , Structure-Activity Relationship , Tretinoin/chemistry , beta Carotene/chemistryABSTRACT
A novel cyclopentenedione, asterredione (1), two new terrecyclic acid A derivatives, (+)-5(6)-dihydro-6-methoxyterrecyclic acid A (2) and (+)-5(6)-dihydro-6-hydroxyterrecyclic acid A (3), and five known compounds, (+)-terrecyclic acid A (4), (-)-quadrone (5), betulinan A (6), asterriquinone D (7), and asterriquinone C-1 (8), were isolated from Aspergillus terreus occurring in the rhizosphere of Opuntia versicolor, using bioassay-guided fractionation. Acid-catalyzed reaction of 2 under mild conditions afforded 4, whereas under harsh conditions 2 yielded 5 and (-)-isoquadrone (9). Catalytic hydrogenation and methylation of 4 afforded 5(6)-dihydro-terrecyclic acid A (10) and (+)-terrecyclic acid A methyl ester (11), respectively. The structures of 1-11 were elucidated by spectroscopic methods. All compounds were evaluated for cytotoxicity in a panel of three sentinel cancer cell lines, NCI-H460 (non-small cell lung cancer), MCF-7 (breast cancer), and SF-268 (CNS glioma), and were found to be moderately active. Cell cycle analysis of 2, 4, and 5 using the NCI-H460 cell line indicated that 4 is capable of disrupting the cell cycle through an apparent arrest to progression at the G(1) and G(2)/M phases in this p53 competent cell line. A pathway for the biosynthetic origin of asterredione (1) from asterriquinone D (7) is proposed.
Subject(s)
Antineoplastic Agents/isolation & purification , Aspergillus/chemistry , Cyclopentanes/isolation & purification , Indoles/isolation & purification , Antineoplastic Agents/pharmacology , Arizona , Cell Cycle/drug effects , Cell Line, Tumor , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Desert Climate , Drug Screening Assays, Antitumor , Humans , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Nervous System Neoplasms , Nuclear Magnetic Resonance, Biomolecular , Opuntia , StereoisomerismABSTRACT
BACKGROUND: Carotenoids in serum vary between countries and within populations with evidence suggesting a qualitative relationship to diet. Breast milk carotenoids furnish a source of vitamin A and potentially provide immunoprotection and other health benefits for infants. There have been numerous studies of milk carotenoid concentrations in undernourished populations; however, carotenoid concentrations have not previously been compared in populations of well-nourished mothers. AIM OF STUDY: To compare concentrations of five major carotenoid groups: alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, and lycopene in breast milk of healthy women from Australia, Canada, Chile, China, Japan, Mexico, the Philippines, the United Kingdom, and the United States, and to qualitatively compare patterns of dietary intake with milk carotenoid concentrations. METHODS: Breast milk collected from healthy lactating women was analyzed for concentrations of five carotenoids and retinol and quantitated relative to total milk lipid. All determinations were performed in a single research laboratory using standardized methodology. Mothers consumed their usual diets and provided a single 24-h dietary recall. RESULTS: Breast milk carotenoid concentrations varied greatly among countries, with the greatest differences in beta-cryptoxanthin (approximately 9-fold) and the least in alpha-carotene and lycopene (approximately 3-fold). Breast milk retinol concentrations varied approximately 2-fold across countries. The provitamin A carotenoids alpha-carotene, beta-carotene, and beta-cryptoxanthin as a group accounted for > 50 % of the carotenoids measured. Total breast milk carotenoids were highest in Japanese and lowest in Philippine mothers. Breast milk beta-carotene concentrations were highest in Chile and lowest in the Philippines. CONCLUSIONS: Patterns of breast milk carotenoids were unique to each country and qualitative patterns reflected the dietary carotenoid supply.
