NOVEL VITAMIN D ANALOGS AS ANTI-CANCER DRUGS

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 EFECT 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: LALPHA-HYDROXY-24-EPI-23-OXAVITAMIN D4, AND PHA-HYDROXY-20-ISO-23-OXA-VITAMIN D4; AND IN THE C20 ISO SERIES: LALPHA-HYDROXY-24-EPI-20-ISO-23-OXAVITAMIN D4 AND LALPHA-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 LINES. FURTHERMORE, A GENERAL TREND OF SAR INDICATES THAT THE 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.