NOVEL VITAMIN D ANALOGS AS ANTI-CANCER DRUGS

1α，25-二羟基维生素D3的侧链修饰类似物已经被 显示抑制骨髓髓系细胞的增殖以及 其他白血病细胞株，并在体外和体外诱导分化 在体内的髓系细胞。这些现象加上低钙血症 活动为抗癌药物提供了希望，这种药物可能会阻止 髓系细胞增殖或分化为良性 单核细胞。我们将合成四种新型的维他命侧链类似物 D2，即在C20-Normal系列中：1α-羟基-24-epi-23- 草维他命D4和1α-羟基-23-恶维他命D4； 系列：1α-羟基-24-环氧丙烷-20-异-23-恶维他明D4和1α-羟基-24-环氧丙烷 羟基-20-异-23-氧-维生素D4。 选择这些化合物的理由是基于类比。 与结构相关的C22-Oxa类似物显示低钙质 诱导HL-60细胞分化的活性和良好效价 台词。此外，特区的大趋势显示，建议的 化合物将没有降钙剂的作用。这些类比将是 在HL-60细胞系实验、小鼠乳腺肿瘤筛查和 钙动员筛查。

Side-chain modified analogs of 1 alpha, 25-dihydroxyvitamin D3 have been shown to suppress proliferation of bone marrow myeloid cells as well as other leukemia cell lines, and effect differentiation both in vitro and in vivo of myeloid cells. These phenomena coupled with low calcemic activity offer promise for an anti-cancer drug which may block proliferation or cause differentiation of myeloid cells into benign monocytes. We will synthesize four novel side-chain analogs of vitamin D2, namely, in the C20- normal series: 1alpha-hydroxy-24-epi-23- oxavitamin D4, and 1alpha-hydroxy-23-oxavitamin D4; and in the C20 iso series: 1alpha-hydroxy-24-epi-20-iso-23-oxavitamin D4 and 1alpha- hydroxy-20-iso-23-oxa-vitamin D4. The rationale for selection of these compounds is based upon analogy with structurally related C22-oxa analogs which show low calcemic activity and good potency in induction of differentiation of HL-60 cell lines. Furthermore, a general trend of SAR indicates that the proposed compounds will be devoid of calcemic effects. These analogs will be assessed in an HL-60 cell line assay, a mouse mammary tumor screen and a calcium mobilization screen.