Calcitriol derivatives with two different side chains at C-20. V. Potent inhibitors of mammary carcinogenesis and inducers of leukemia differentiation.
Calcitriol is implicated in many cellular functions including cellular growth and differentiation, thus explaining its antitumor effects. It was shown that gemini, the calcitriol derivative containing two side chain at C20, is also active in gene transcription with enhanced antitumor 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 1alpha-fluoro A-ring 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. On the basis of these evaluations, we selected as lead compound a 20(R) gemini, related to calcitriol in terms of it is 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.
Maehr
Hubert
H
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA. hubert.maehr@verizon.net
Lee
Hong Jin
HJ
Perry
Bradford
B
Suh
Nanjoo
N
Uskokovic
Milan R
MR
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000473:pathology*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation
D000970:Antineoplastic Agents; D002117:Calcitriol
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