Abstract

Retinoids, particularly retinoic acid, are able to suppress, prevent, and reverse the transformation of premalignant cells to the malignant state. Consequently, they have potential value as drugs for the chemoprevention and treatment of cancer. However, those retinoids tested to date have substantial toxic side effects. Therefore, new retinoids are required. The synthesis of a series of novel and potentially more effective retinoids is proposed. These compounds have conformational restrictions and electronic variations in the tetraene chain region of the retinoid skeleton. Compounds will be screened for chemopreventive efficacy with the ornithine decarboxylase and antipapilloma tumor assays. Their binding affinity to cellular retinoic acid-binding protein will be determined. Active compounds will be submitted to NCI for additional testing.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030512-06
Application #
3169276
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1981-09-01
Project End
1988-12-31
Budget Start
1987-01-01
Budget End
1987-12-31
Support Year
6
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
Sri International
Department
Type
DUNS #
City
Menlo Park
State
CA
Country
United States
Zip Code
94025

  Publications

Willhite, C C; Dawson, M I (1990) Structure-activity relationships of retinoids in developmental toxicology. IV. Planar Cisoid conformational restriction. Toxicol Appl Pharmacol 103:324-44
Howard, W B; Sharma, R P; Willhite, C C et al. (1990) Binding affinities of retinoids to fetal cellular retinoic acid-binding protein (CRABP) in relation to their teratogenic potency in hamsters. Biochem Pharmacol 40:643-8
Norman, A W; Zhou, J Y; Henry, H L et al. (1990) Structure-function studies on analogues of 1 alpha,25-dihydroxyvitamin D3: differential effects on leukemic cell growth, differentiation, and intestinal calcium absorption. Cancer Res 50:6857-64
Dawson, M I; Hobbs, P D (1990) Synthetic retinoid acid analogs: handling and characterization. Methods Enzymol 189:15-43
Sani, B P; Wille Jr, J J; Dawson, M I et al. (1990) Biologically active aromatic retinoids bearing azido photoaffinity-labeling groups and their binding to cellular retinoic acid-binding protein. Chem Biol Interact 75:293-304
Singh, R K; Sani, B P; Dawson, M I et al. (1989) Affinity purification of cellular retinoic acid-binding protein on 14-carboxy-13-cis-retinamide-sepharose 4B. Biochem J 262:917-22
Dawson, M I; Hobbs, P D; Derdzinski, K A et al. (1989) Effect of structural modifications in the C7-C11 region of the retinoid skeleton on biological activity in a series of aromatic retinoids. J Med Chem 32:1504-17
Howard, W B; Willhite, C C; Dawson, M I et al. (1988) Structure-activity relationships of retinoids in developmental toxicology. III. Contribution of the vitamin A beta-cyclogeranylidene ring. Toxicol Appl Pharmacol 95:122-38
Dawson, M I; Chao, W R; Helmes, C T (1987) Inhibition by retinoids of anthralin-induced mouse epidermal ornithine decarboxylase activity and anthralin-promoted skin tumor formation. Cancer Res 47:6210-5
Mehta, R G; Schiff, L J; Moore, S J et al. (1986) Cellular retinoic acid-binding protein and its relationship to the biological activity of four synthetic retinoids in hamster tracheal organ culture. In Vitro Cell Dev Biol 22:164-8

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