Conformationally restricted retinoids.
Conformationally restricted retinoids.
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构象限制的类维生素A。
DOI：
10.1021/jm00377a022
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发表时间：
1984
影响因子：
7.3
通讯作者：
Schiff,LJ
中科院分区：
文献类型：
--
作者：
Dawson,MI;Hobbs,PD;Derdzinski,K;Chan,RL;Gruber,J;Chao,WR;Smith,S;Thies,RW;Schiff,LJ
合成了一系列构象受限的类维生素A，并在两种测定中进行筛选，这两种测定用于测量类维生素A控制细胞分化的能力，即逆转维生素A缺乏仓鼠气管器官培养物中的角化和抑制肿瘤促进剂诱导小鼠表皮鸟氨酸脱羧酶。这些化合物的键对应于视黄酸（1）的E-四烯链的选定键，通过包含在芳环中而保持平面顺式构象。4-[（E）-2-甲基-4-（2，6，6-三甲基环己烯基）-1，3-丁二烯基]苯甲酸（2）的间位取代的类似物3在两种测定中的活性远低于2。相反，2（4）的乙烯基同系物和7，8-二氢和7，8-亚甲基类似物（5和6）具有与2相当的活性。还筛选了4-[（E）-2-（1，1，4，4-四甲基-1，2，3，4-四氢-6-萘基）丙烯基]苯甲酸（7）的类似物。将7的四氢萘环替换为苯并降冰片烯基（9）会显著降低活性，从9中去除乙烯基甲基也是如此（10）。用环丙烷环（12）取代9的丙烯基也降低了活性。用4，4-二甲基-3，4-二氢-2-[1-苯并吡喃]和4-苯并噻喃环（13和14）取代7的四氢萘环也降低了活性。在芳环中包含1的7，9双键系统（15和16）降低活性，而在芳环中包含5，7双键系统增强活性（7和19）。芳环（2和18）中包含11、13和9、11、13双键系统也使活性降低至低于1。维甲酸7、13、14和19抑制小鼠乳头状瘤的形成。毒性试验表明，7比1、13、14和19的毒性大，19比1的毒性大，13和14比1的毒性小。由于维甲酸等维甲酸类化合物具有调节上皮细胞分化的能力，因此在治疗痤疮、银屑病等增生性皮肤病和癌症的化学预防方面具有潜在的应用价值。1维甲酸（1）通常以四烯侧链的E双键为反式的构象描述，如表I所示。然而，这种构象不一定是1在控制分化中所呈现的构象。作为合成更有活性的类维生素A和研究其结构-活性关系的计划的一部分，我们合成了一系列构象受限的类维生素A，其结构见表I。在这些化合物中，与1的四烯链的键相对应的某些键通过包含在芳环中而保持顺式构象。在某些情况下，构象被环丙烷环取代的E双键扭曲。这些化合物在用于测量类维生素A调节细胞分化的能力的两种生物测定中筛选，即（1）仓鼠气管器官培养物中角化的逆转（TOC测定）和（2）肿瘤促进剂12-0-十四酰基佛波醇-13-乙酸酯对小鼠表皮中鸟氨酸脱羧酶诱导的抑制（ODC测定）。2，3我们现在报告这些化合物的合成和生物测试结果。
A series of conformationally restricted retinoids was synthesized and screened in two assays used to measure the ability of retinoids to control cell differentiation, namely, the reversal of keratinization in tracheal organ culture from vitamin A deficient hamsters and the inhibition of the induction of mouse epidermal ornithine decarboxylase by a tumor promoter. These compounds had bonds corresponding to selected bonds of the E-tetraene chainof retinoic acid (1) held in a planar cisoid conformation by inclusion in an aromatic ring. The meta-substituted analogue 3 of 4-[(E)-2-methyl-4-(2, 6, 6-trimethylcyclohexenyl)-l, 3-butadienyl] benzoic acid (2) was far less active than 2 in both assays. In contrast, the vinyl homologue of 2 (4) and the 7, 8-dihydro and 7, 8-methano analogues (5 and 6) had activity comparable to that of 2. Analogues of 4-[(E)-2-(l, l, 4, 4-tetramethyl-l, 2, 3, 4-tetrahydro-6-naphthyl) propenyl] benzoic acid (7) were also screened. Replacementof the tetrahydronaphthalene ring of 7 by a benzonorbornenyl group (9) significantly reduced activity, as did removal of the vinylic methyl group from 9 (10). Replacement of the propenyl group of 9 by a cyclopropane ring (12) also reduced activity. Replacement of the tetrahydronaphthalene ring of 7 by 4, 4-dimethyl-3, 4-dihydro-2íf-l-benzopyran and-benzothiopyran rings (13 and 14) also decreased activity. Inclusion of the 7, 9 double bond system of 1 in an aromatic ring (15 and 16) reduced activity, whereas inclusion of the 5, 7 double bond system in an aromatic ring enhanced activity (7 and 19). Inclusion of the 11, 13 and 9, 11, 13 double bond systems in aromatic rings (2 and 18) also reduced activity below that of 1. Retinoic acid, 7, 13, 14, and 19 inhibited papilloma tumor formation inmice. Toxicity testing indicated that 7 was more toxic than 1, 13, 14, and19, 19 was more toxic than 1, and 13 and 14 were less toxic than 1.Because of their ability to regulate epithelial cell dif-ferentiation, the retinoids, such as retinoic acid, have therapeutic potential for the treatment of proliferative skin diseases, such as acne and psoriasis, and the chemopre-vention of cancer. 1 Retinoic acid (1) is usually depicted in a conformation in which the E double bonds of the tetraene side chain are transoid, as shown in Table I. However, this conformation is not necessarily the one that 1 assumes in controlling differentiation. As part of a program to synthesize more active retinoids and study their structure-activity relationships, we have synthesized a series of conformationally restricted retinoids, the structures of which are shown in Table I. In these com-pounds certain bonds corresponding to those of thetet-raene chain of 1 are held in a cisoid conformation by inclusion in an aromatic ring. In certain cases, the conformation is distorted by replacement of an E double bond by a cyclopropane ring. These compounds were screened in two bioassays used to measure the ability of retinoids to regulate cell differentiation, namely,(1) the reversal of keratinization in hamster tracheal organ culture (TOC assay) and (2) the inhibition of the induction of ornithine decarboxylase in mouse epidermis by the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (ODC assay). 2, 3 We now report the syntheses and biological testing results for these compounds.