Convenient and versatile route to 2-alkyl-19-nor-analogues of calcitriol

Since decades, researchers have been intrigued by 1α,25-dihydroxy vitamin D3 (calcitriol) in various important cellular processes. Apart from its well-known role in calcium- and phosphate-regulation, this steroid metabolite presents also a remarkably broad spectrum of transitions. Most notably, the ability to inhibit cell growth and stimulate cell differentiation upon binding to the vitamin D receptor (VDR) turns calcitriol into a potential drug candidate. Moreover, the VDR- receptor’s found in over 30 different tissues in the human body, including various tumors, opening up new therapeutic areas. However, dosing test animals with the required supra-fysiological amounts of calcitriol causes acute hypercalcemia leading to bone deformation, hardening of soft organs and eventually mortality.Labour-intensive SAR studies on the complex vitamin D scaffold established that calcemic activities could be separated from the therapeutic activities by using analogues thereof. In fact, analogues are now in advanced stages of research, e.g. inecalcitol is in clinical phase II for the treatment of chronic lymphocytic leukemia and Daivonex (calcipotriol, Leo pharmaceuticals) is already available as a treatment for hyperproliferative disorder (psoriasis).We have shown that two calcitriol modifications, where a methyl or ethyl group is introduced at the 2α-position, had little calcemic effects in mice, while remaining potent in in vitro assays on inhibition of human cancer cell growth. However, the initially developed synthetic routes were highly inefficient and only gave sub-milligram amounts of these analogues. Here, we will present a practical route for novel A-ring building blocks, starting from D-(-)-quinic acid allowing larger scale synthesis of these sort of analogues, as required for studies in animal models of various diseases. Such extensive in vivo tests on these promising 2-alkyl-14,20-bisepi-19-nor-23-yne-analogues are now in progress at the KULeuven.

Jaar van publicatie:2013