维甲类化合物的研究 IV.双叔丁基苯类化合物的设计合成和构效关系

STUDIES ON RETINOIDS IV. DESIGN, SYNTHESIS AND STRUCTURE ACTIVITY RELATIONSHIPS OF DI t BUTYLPHENYL COMPOUNDS

以３，５双叔丁基４羟基苯基为结构单元设计合成了取代的酰芳胺、芳酯和查尔酮类化合物，模拟全反式维甲酸的分子形状、长度和功能基的空间配置，并研究对细胞诱导分化的活性。结果表明分子一端的疏水性基团，另一端羧基的存在以及分子的共轭性，是呈现诱导分化活性的必要和充分的因素，缺少其中任何一个则失去活性，而且分子的构象、形状和基团的配置也起关键作用。芳酰胺类的Ｎ甲基化产物的稳定构象是两个芳环呈顺式排布，使分子成弯曲状，而不呈反式的伸展形式，以致与全反式维甲酸分子的伸展形状不同，这是它失去活性的原因。本工作发现化合物Ｎｏ４ｆ，４ｇ，７，１３，３２，３７和３８等具有显著的细胞诱导分化作用。

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 synthsized, which mimic the molecular shape, size, and spacial disposition of functional groups of retinoic acid. The general structure is as follows: 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.