NOVEL VITAMIN D ANALOGS AS ANTI-CANCER DRUGS

1 α，25-二羟基维生素D3的侧链修饰的类似物已经被 显示抑制骨髓髓样细胞的增殖以及 其他白血病细胞系，并在体外和 在体内的骨髓细胞。这些现象加上低钙 活动提供了一种抗癌药物的希望， 增殖或导致骨髓细胞分化为良性 单核细胞我们将合成四个新的维生素C侧链类似物， D2，即在C20-正常系列中：1 α-羟基-24-表-23- oxavitamin D4和1 α-羟基-23-oxavitamin D4;在C20异 系列：1 α-羟基-24-表-20-异-23-氧杂维生素D4和1 α- 羟基-20-异-23-氧-维生素D4。 选择这些化合物的基本原理是基于类比 与结构上相关的C22-oxa类似物， 对HL-60细胞有良好的诱导分化作用 线此外，SAR的总体趋势表明， 化合物将没有钙效应。这些类似物将是 在HL-60细胞系测定、小鼠乳腺肿瘤筛选和 钙动员筛选。

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.