Calcitriol (25-Hydroxyvitamin D3;1,25D), the major metabolite of vitamin D3 circulating in the blood, undergoes hydroxylation at C-1 in the kidneys to its biologically active form, 1?,25-dihydroxyvitamin D3 [1,25D, calcitriol. This natural hormone exhibits a broad spectrum of activities, ranging from its classical functions in regulating of mineral homeostasis (calcium and phosphorous metabolism), to numerous antiproliferative, pro-differentiative, and immunomodulatory activities. Most of its actions are mediated by a nuclear transcription factor known as the vitamin D nuclear receptor (VDR). The presence of VDR in a great variety of tissues and cells, including brain, skin, colon, kidney, pancreas and breast among others, makes it a therapeutic target for diseases such as cancer, hyperparathyroidism, psoriasis, rickets and autoimmune diseases. However, the intrinsic hypercalcemic effect associated with pharmacological doses of 1,25D precludes its use in therapeutical applications. This has induced an extensive effort in chemical synthesis of 1,25D analogues that display reduced calcemic activity but retain powerful antiproliferative activity. The natural side chain of 1,25D has been the main target of chemical modifications. Modifications at the A-ring and more recently non-steroidal analogs of vitamin D have also been described.
Over the past 30 years, the research group headed by Dr. Antonio Mouriño has dedicated efforts to the development of convergent synthetic routes leading to vitamin D3 analogues (http://webspersoais.usc.es/persoais/antonio.mourino/professor_mourino.html).
In this context, and as part of a collaboration recently initiated (USC-LAQV-UP; http://www.fc.up.pt/orchids/), emerged the innovative idea of designing new secosteroids analogues containing silicon units in the side chain with selective properties and low or negligible calcemic effects for treatment of cancer, osteoporosis, psoriasis and vitamin D-resistant rickets.
Taking advantage of the expertise of each team, the synthetic tasks will be performed by the PI team at UP. Complimentary theoretical studies of molecular modeling (docking), concerning the affinity capacity of the synthesized analogues with the VDR, will be performed at USC and should allow the assessment of the most promising compounds.
As far as we know, there is no publication of silicon-containing vitamin D analogues, nor groups in Portugal dedicated to the synthesis of new secoesteroidal analogues as potential drugs.
 Hence, the teams gathered in this project (from UP and USC) have the expertise and synergic facilities in the areas of theoretical studies for molecular modelling, organic synthesis and, independently, biological assays to develop the project with a high degree of success.