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[Studies on retinoids. IV. Design, synthesis and structure-activity relationships of di-t-butylphenyl compounds]. 1997

Z R Guo, and Q Z Liu, and F M Chu, and M M Wang, and S Q Pi, and G Z Yang, and R Han, and L J Xia, and X Q He
Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050.

Retinoic acid and its analogues play important roles in modulating cell growth, differentiation, immunity and apoptosis. Clinically they are used for cancer chemoprevention and chemotherapy. Based upon the moiety of 3,5-di-t-butyl-4-hydroxy phenyl ring, a series of substituted aromatic amide, ester and chalcones were designed and synthesized, which mimic the molecular shape, size, and spacial disposition of functional groups of retinoic acid. The general structure is as follows: [formula: see text] where R stands for hydrogen atom or methyl group, Y is the linkage -CONH-, -NHCO-, -COO-, -COCH = CH-, or a member of a heterocycle, X represents various substituents at different positions. The SAR indicates that the presence of hydrophobic group(s) at one end of the molecule, and a carboxyl group at the other end, and a conjugative system of molecule are necessary and full prerequisite for exhibiting activity. Loss of any one factor of them will abolish the activity. Being obligatory for anti-oxidative effect, the phenolic hydroxy group does not convey biological activity, because after methylation of the hydroxy group the compound increases the differentiation-inducing activity and loses the anti-oxidative effect, indicating that there is no correlation between the two activities. With a stable conformation of two phenyl rings with cis-conformation N-methylated acyl amide (No. 30) features in bent shape of the molecule, instead of an extended conformer, which is taken by the non-N-methylated partner and all-trans retinoic acid. A bent conformer of No. 30 accounts for the inactivity. In this paper compounds No. 4f, 4g, 5a, 7, 13, 32, 37, and 38 exhibited significant activity among them 4-[3-(3, 5-di-t-4-methoxyphenyl)-3-oxo-1-propenyl] benzoic acid (No. 38) showed high activity comparable to that of retinoic acid. The pharmacological action of No. 38 is under investigation.

UI MeSH Term Description Entries
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D002471 Cell Transformation, Neoplastic Cell changes manifested by escape from control mechanisms, increased growth potential, alterations in the cell surface, karyotypic abnormalities, morphological and biochemical deviations from the norm, and other attributes conferring the ability to invade, metastasize, and kill. Neoplastic Transformation, Cell,Neoplastic Cell Transformation,Transformation, Neoplastic Cell,Tumorigenic Transformation,Cell Neoplastic Transformation,Cell Neoplastic Transformations,Cell Transformations, Neoplastic,Neoplastic Cell Transformations,Neoplastic Transformations, Cell,Transformation, Cell Neoplastic,Transformation, Tumorigenic,Transformations, Cell Neoplastic,Transformations, Neoplastic Cell,Transformations, Tumorigenic,Tumorigenic Transformations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001565 Benzoates Derivatives of BENZOIC ACID. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the carboxybenzene structure. Benzoate,Benzoic Acids,Acids, Benzoic
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014212 Tretinoin An important regulator of GENE EXPRESSION during growth and development, and in NEOPLASMS. Tretinoin, also known as retinoic acid and derived from maternal VITAMIN A, is essential for normal GROWTH; and EMBRYONIC DEVELOPMENT. An excess of tretinoin can be teratogenic. It is used in the treatment of PSORIASIS; ACNE VULGARIS; and several other SKIN DISEASES. It has also been approved for use in promyelocytic leukemia (LEUKEMIA, PROMYELOCYTIC, ACUTE). Retinoic Acid,Vitamin A Acid,Retin-A,Tretinoin Potassium Salt,Tretinoin Sodium Salt,Tretinoin Zinc Salt,Vesanoid,all-trans-Retinoic Acid,beta-all-trans-Retinoic Acid,trans-Retinoic Acid,Acid, Retinoic,Acid, Vitamin A,Acid, all-trans-Retinoic,Acid, beta-all-trans-Retinoic,Acid, trans-Retinoic,Potassium Salt, Tretinoin,Retin A,Salt, Tretinoin Potassium,Salt, Tretinoin Sodium,Salt, Tretinoin Zinc,Sodium Salt, Tretinoin,Zinc Salt, Tretinoin,all trans Retinoic Acid,beta all trans Retinoic Acid,trans Retinoic Acid
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D018360 Crystallography, X-Ray The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) X-Ray Crystallography,Crystallography, X Ray,Crystallography, Xray,X Ray Crystallography,Xray Crystallography,Crystallographies, X Ray,X Ray Crystallographies
D018922 HL-60 Cells A promyelocytic cell line derived from a patient with ACUTE PROMYELOCYTIC LEUKEMIA. HL-60 cells lack specific markers for LYMPHOID CELLS but express surface receptors for FC FRAGMENTS and COMPLEMENT SYSTEM PROTEINS. They also exhibit phagocytic activity and responsiveness to chemotactic stimuli. (From Hay et al., American Type Culture Collection, 7th ed, pp127-8) HL60 Cells,Cell, HL60,Cells, HL60,HL 60 Cells,HL-60 Cell,HL60 Cell

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