Kensler T W, Dolan P M, Gange S J, Lee J K, Wang Q, Posner G H
Department of Environmental Health Sciences and Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA.
Carcinogenesis. 2000 Jul;21(7):1341-5.
Development of vitamin D analogs (deltanoids) as chemopreventive agents requires separation of desirable antiproliferative and pro-differentiating activities from the undesirable calcemic activity also found in the hormone calcitriol (1 alpha, 25-dihydroxyvitamin D(3)). Therefore, several conceptually new deltanoids were synthesized with modifications to the 1alpha- and/or 25-hydroxyl groups, positions traditionally considered essential for stimulating biological responses. In this study, 1 beta-hydroxymethyl-3-epi-25-hydroxyvitamin D(3), a non-calcemic CH(2) homolog of the natural hormone with antiproliferative activity in vitro, was ineffective as an inhibitor of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced induction of ornithine decarboxylase activity in mouse epidermis. However, a hybrid analog incorporating not only the calcemia-ablating 1 beta-hydroxymethyl alteration, but potentiating C,D ring 16-unsaturation and side chain 24,24-fluorination and 26, 27-homologation was found to be as effective as calcitriol. Several non-calcemic 24- or 25-t-butyl sulfones, some containing side chain fluorination but all lacking the 25-hydroxyl group, were also shown to be active in this assay. Three sulfones and the 1 beta-hydroxymethyl hybrid were evaluated as inhibitors of multistage carcinogenesis in mouse skin. Female CD-1 mice were initiated with a single dose of 7,12-dimethylbenz[a]anthracene and then promoted twice weekly for 20 weeks with TPA. Deltanoids were applied topically 30 min before TPA. Unlike calcitriol, none of the atypical deltanoids affected body weight gain in these animals. Minimal effects on urinary calcium excretion were observed following chronic treatment with these analogs. All deltanoids inhibited the incidence and multiplicity of papilloma formation, with the hybrid analog showing the greatest efficacy. With this deltanoid, tumor incidence was significantly reduced by 28% and tumor multiplicity by 63%. These results, coupled with the rich chemical diversity available in side chain sulfur-containing deltanoids, particularly when combined with A ring modifications such as 1 beta-hydroxylalkyl groups, provide important new advances in the fundamental understanding of chemical structure-biological activity relationships as well as more potent and safe vitamin D analogs for cancer chemoprevention and other medicinal uses.
将维生素D类似物（三角类化合物）开发为化学预防剂，需要将理想的抗增殖和促分化活性与在激素骨化三醇（1α,25 - 二羟基维生素D₃）中也存在的不良血钙活性区分开来。因此，合成了几种概念上新颖的三角类化合物，对1α - 和/或25 - 羟基进行了修饰，这些位置传统上被认为对刺激生物反应至关重要。在本研究中，1β - 羟甲基 - 3 - 表 - 25 - 羟基维生素D₃，一种天然激素的非血钙性CH₂同系物，在体外具有抗增殖活性，但作为12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）诱导的小鼠表皮鸟氨酸脱羧酶活性诱导的抑制剂无效。然而，一种不仅包含消除血钙活性的1β - 羟甲基改变，还具有增强C、D环16 - 不饱和以及侧链24,24 - 氟化和26,27 - 同系化的杂合类似物，被发现与骨化三醇一样有效。几种非血钙性的24 - 或25 - 叔丁基砜，有些含有侧链氟化但都缺乏25 - 羟基，在该试验中也显示出活性。评估了三种砜和1β - 羟甲基杂合物作为小鼠皮肤多阶段致癌作用的抑制剂。雌性CD - 1小鼠单次给予7,12 - 二甲基苯并[a]蒽，然后每周用TPA促进两次，共20周。在TPA之前30分钟局部应用三角类化合物。与骨化三醇不同，这些非典型三角类化合物均未影响这些动物的体重增加。长期用这些类似物治疗后，观察到对尿钙排泄的影响最小。所有三角类化合物均抑制乳头瘤形成的发生率和多发性，杂合类似物显示出最大的功效。使用这种三角类化合物，肿瘤发生率显著降低28%，肿瘤多发性降低63%。这些结果，再加上含侧链硫的三角类化合物具有丰富的化学多样性，特别是当与诸如1β - 羟烷基等A环修饰结合时，为化学结构 - 生物活性关系的基础理解以及更有效和安全的用于癌症化学预防和其他医学用途的维生素D类似物提供了重要的新进展。
