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Relationship between Binding Affinities to Cellular Retinoic Acid-binding Protein and Biological Potency of a New Series of Retinoids

Kettering Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35255-5305 [B. P. S.]; Life Sciences Division, SRI International, Menlo Park, California 94025 [M. I. D., P. D. H., R. L-S. C.]; and IIT Research Institute, Chicago, Illinois 60616 [L. J. S.]

Binding affinities of a new and unusual series of retinoic acid analogues to cellular retinoic acid-binding protein, a possible mediator of their biological function in the control of differentiation and tumorigenesis, and to serum albumin, their plasma transport protein, were determined. Also, biological activity of these retinoids in the reversal of keratinization in hamster tracheal organ cultures was assessed and compared with their binding affinities. Analogues that possessed high biological activity showed high binding efficiency to cellular retinoic acid-binding protein. Those that were biologically less active were poor binders to the binding protein. Three retinoids, 4657-57, 3920-59, and 4445-75, which showed 90 to 100% binding efficiency of that of retinoic acid for cellular retinoic acid-binding protein expressed high biological activity detectable in the range of 10^-10 M as against 10^-11 M for retinoic acid. The correlation noticed in these two activities not only enhances the confidence in the two assay procedures but also paves the way for design and development of potential chemopreventive agents. No apparent differences were observed in the binding affinities of the retinoids to binding proteins of a normal tissue or a tumor tissue. No correlation existed between the binding affinities of these retinoids to serum albumin and their biological activity. Structure-activity relationships of the retinoids in relation to their binding affinities and biological activities have been discussed.

¹ Recipient of Biomedical Research Support Grant 2SO7 RR0567-05 from the NIH. To whom requests for reprints should be addressed, at Biochemistry Department, Southern Research Institute, P.O. Box 55305, Birmingham, Ala. 35255-5305.

² Recipient of NIH USPHS Grant CA30512 and Contract NO1-CP-5600.

³ Recipient of Contract NO1-CP-5610 from the Division of Cancer Cause and Prevention, National Cancer Institute, NIH.

Received 6/ 3/83. Accepted 10/ 7/83.