[Studies on retinoids. IV. Design, synthesis and structure-activity relationships of di-t-butylphenyl compounds].
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.
Guo
Z R
ZR
Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050.
Liu
Q Z
QZ
Chu
F M
FM
Wang
M M
MM
Pi
S Q
SQ
Yang
G Z
GZ
Han
R
R
Xia
L J
LJ
He
X Q
XQ
D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D018360:Crystallography, X-Ray; D018922:HL-60 Cells; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
C442165:4-(3-(3, 5-di-t-4-methoxyphenyl)-3-oxo-1-propenyl)benzoic acid; D001565:Benzoates; D014212:Tretinoin