Spruce L W, Gale J B, Berlin K D, Verma A K, Breitman T R, Ji X H, van der Helm D
Department of Chemistry, Oklahoma State University, Stillwater 74078.
J Med Chem. 1991 Jan;34(1):430-9. doi: 10.1021/jm00105a065.
In this study, 13 heteroarotinoids were synthesized. The key step in each preparation was the condensation of the appropriate chroman-, thiochroman-, or benzothienyl-substituted phosphorus ylide, obtained from the independent synthesis of the corresponding phosphonium salts, with selected polyene-substituted aldehyde esters. Nine of these heterocycles contained a thiochroman group, two had a chroman group, and two others had a benzothienyl system. Screening of the compounds was with one of two assays. One assay measured the ability of a retinoid to inhibit the phorbol ester induced increase of mouse epidermal ornithine decarboxylase (ODC) activity. The other assay measured retinoid-induced differentiation of the human myoloid leukemia cell line HL-60. In the ODC assay, all thirteen compounds were screened. The most active heteroarotinoids were ester 10 [methyl (E)-4-[2-(2,2,4,4-tetramethylthiochroman-6-yl)-1- propenyl]benzoate] and acid 11 [(E)-4-[2-(2,2,4,4-tetramethyl-3,4- dihydro-2H-1- benzothiopyran-6-yl)-1-propenyl]benzoic acid]. Both of these retinoids had ID50 values (dose required for half-maximal inhibition of phorbol ester induced ODC activity) of about 0.3 nmol. In comparison, the ID50 value for trans-retinoic acid (1) was 0.12 nmol while the ID50 values for acids 7 and 9, namely (2Z,4E,6E)-3,7-dimethyl-7-(4,4-dimethyl-thiochroman -6-yl)-2,4,6-heptatrienoic acid and (2E,4E,6E)-3,7-dimethyl-7-(2,2,4,4-tetramethylthiochroman -6-yl)-2,4,6- heptatrienoic acid, respectively, were about 3.5 nmol. Heteroarotinoids 8 and 12-17 had ID50 values of 35 nmol or greater. With a thiochroman unit, the most active acids in decreasing order of activity in the ODC assay were 7 greater than 9 greater than 8. Thus, simple replacement of the terminal propenyl system [C(16,17,18)] in 7 with a cyclopropyl group produced acid 8 [(2E,4E,6E)-7-methyl-7-(4,4-dimethylthiochroman-6-yl)- 2,3-methylene-4,6-heptadienoic acid with markedly reduced activity. With a benzoic acid group as part of the structure attached to the thiochroman unit, the ODC activity was enhanced as shown in 10 and 11. The combination of the 2,2,4,4-tetramethylthiochroman group and the benzoic acid (or ester) terminal group seemed to enhance the biological action which resembles that found with (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)- 1-propenyl]benzoic acid (TTNPB, 6b), a well-known model system.(ABSTRACT TRUNCATED AT 400 WORDS)
在本研究中，合成了13种杂合维甲酸。每种制备方法的关键步骤是将通过独立合成相应鏻盐得到的适当的色满、硫色满或苯并噻吩基取代的磷叶立德与选定的多烯取代的醛酯缩合。这些杂环化合物中有9个含有硫色满基团，2个含有色满基团，另外2个含有苯并噻吩体系。化合物的筛选采用两种测定方法之一。一种测定方法是测量类视黄醇抑制佛波酯诱导的小鼠表皮鸟氨酸脱羧酶（ODC）活性增加的能力。另一种测定方法是测量类视黄醇诱导的人髓样白血病细胞系HL-60的分化。在ODC测定中，对所有13种化合物进行了筛选。活性最高的杂合维甲酸是酯10 [甲基（E）-4-[2-(2,2,4,4-四甲基硫色满-6-基)-1-丙烯基]苯甲酸酯]和酸11 [(E)-4-[2-(2,2,4,4-四甲基-3,4-二氢-2H-1-苯并噻喃-6-基)-1-丙烯基]苯甲酸]。这两种类视黄醇的ID50值（抑制佛波酯诱导的ODC活性达到半数最大抑制所需的剂量）均约为0.3 nmol。相比之下，反式维甲酸（1）的ID50值为0.12 nmol，而酸7和酸9的ID50值，即(2Z,4E,6E)-3,7-二甲基-7-(4,4-二甲基硫色满-6-基)-2,4,6-庚三烯酸和(2E,4E,6E)-3,7-二甲基-7-(2,2,4,4-四甲基硫色满-6-基)-2,4,6-庚三烯酸，分别约为3.5 nmol。杂合维甲酸8和12 - 17的ID50值为35 nmol或更高。对于含有硫色满单元的化合物，在ODC测定中活性由高到低的最活泼的酸依次为7大于9大于8。因此，将7中的末端丙烯基体系[C(16,17,18)]简单地用环丙基取代，得到酸8 [(2E,4E,6E)-7-甲基-7-(4,4-二甲基硫色满-6-基)-2,3-亚甲基-4,6-庚二烯酸]，其活性显著降低。当苯甲酸基团作为连接硫色满单元的结构的一部分时，如10和11所示，ODC活性增强。2,2,4,4-四甲基硫色满基团和苯甲酸（或酯）末端基团的组合似乎增强了生物学作用，这与已知的模型体系（E）-4-[2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)-1-丙烯基]苯甲酸（TTNPB，6b）相似。（摘要截选至400字）
