Calcitriol is implicated in many cellular functions including cellular growth and differentiation thus explaining its anti-tumor effects. It was shown that gemini, the calcitriol derivative containing two side chain at C20, is also active in gene transcription with enhanced anti-tumor activity. We have now further optimized both the A-ring and the two side chains. The chemical structures of the resulting 18 geminis were correlated with biological activities. Those containing the 1α-fluoro Aring are the least active. Those featuring 23-yne and 23(E) side-chains are generally more active in human breast cancer-cell growth inhibition and human leukemia-cell differentiation induction than their 23(Z) counterparts. Based on these evaluations we selected as lead compound a 20(R) gemini, related to calcitriol in terms of it's A-ring, where one side chain was modified by introduction of a 23-yne function and replacement of the geminal methyl groups with trifluoromethyl groups, the other created by extension of C21 with a 3-hydroxy-3-trideuteromethyl-4,4,4-trideutero-butyl moiety.