Retinobenzoic acids. 2. Structure-activity relationships of chalcone-4-carboxylic acids and flavone-4'-carboxylic acids.
The structure-activity relationships of (E)-chalcone-4-carboxylic acids, which are retinoidal benzoic acids represented by R-Ph-X-Ph-COOH (4, X = -COCH = CH-), are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60. The activity was increased by the substitution of a bulky alkyl group(s) (R), and among such compounds, (E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]benzoic acid (Ch55) and (E)-4-[3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1 -propenyl]benzoic acid (Ch80) are several times more active than retinoic acid. Though the stable conformer of chalcone derivatives is linear (s-cis form), the conformationally restricted analogue 4-(6,7,8,9-tetrahydro-6,6,9,9-tetramethyl-4H-4-oxonaphtho[2,3-b]py ran-2-yl)benzoic acid (Fv80) is more active than Ch80. While the effect of introduction of an oxygen atom varied, 4-[1-hydroxy-3-oxo-3-(5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl-2 - naphthalenyl)-1-propenyl]benzoic acid (Re80), regarded as a derivative of Ch80 with two additional hydroxyl groups, has very strong activity.
Kagechika
H
H
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Kawachi
E
E
Hashimoto
Y
Y
Shudo
K
K
D002264:Carboxylic Acids / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D008968:Molecular Conformation; D015394:Molecular Structure; D011427:Propiophenones / Q000031:analogs & derivatives / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D002264:Carboxylic Acids; D005419:Flavonoids; D011427:Propiophenones; D002599:Chalcone