Novel hybrid analogs of the active hormone 1alpha,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation

The natural hormone 1alpha,25-dihydroxyvitamin D3 (calcitriol, 1) plays an important role in several biological functions, including calcium homeostasis and the ability to inhibit the proliferation of various types of cancer. Synthetic analogs of calcitriol, which maintain antiproliferative activity while diminishing unwanted calcium response, have been shown to be attractive candidates for the treatment of a diverse range of human diseases such as skin psoriasis, prostate cancer, breast and colon cancers.; New side chain 24- and 25-sulfone, sulfoxide, and sulfonamide analogs were synthesized and biologically evaluated to explore what specific functional groups of these analogs are critical for eliciting the desired biological response. Some of them displayed in vitro antiproliferative active toward murine keratinocytes, and they are also potent inhibitors of the human cytochrome P450C24 (CYP24) hydroxylase. Phenyl sulfone analog (+)-97a was found to be approximately 10 times more active (27 nM) in CYP24 inhibition than the standard ketoconazole (300 nM).; Copper(I)-catalyzed cycloaddition of a vitamin D side chain terminal acetylene with phenyl azide and separately with a vitamin D side chain azide successfully produced the corresponding 1,2,3-triazole analogs of 1alpha-hydroxyvitamin D3 in good yields. The dimer triazole 162 as a chemical inducer of vitamin D3 protein receptor (VDR) dimerization was designed for exploring and possibly exploiting its role in transcription control. Monomer phenyl triazole 161 and dimer triazole 162 were found to be less antiproliferative active than calcitriol over a whole range of concentrations. However, this is the first report of 'click' chemistry in the vitamin D field and the first synthesis of a vitamin D dimeric analog in which the monomeric vitamin D units are linked via a side chain heteroaromatic ring. This work will allow the design and preparation of dimers with a more flexible linker of modulated length with the purpose of optimizing the vitamin D3-VDR interaction.; A series of new side chain 25-ketone analogs have been synthesized, some of which are considerably more antiproliferative in vitro than the hormone calcitriol even at physiologically relevant low nanomolar concentrations and less calcemic than calcitriol in vivo. We have found that small structural changes such as the replacement of the natural tertiary hydroxyl group by a methyl group and simple functional group alterations (e.g., carbonyl group insertion at either C-24 or C-25) in the large natural hormone molecule elicit desirable biological responses.