Vitamin D esters are the major form of vitamin D produced by UV irradiation in mice.

The primary source of vitamin D3 for humans is that produced in skin by ultraviolet irradiation. Ultraviolet (UV) B (UVB, 280-310 nm) light causes the isomerization of 7-dehydrocholesterol (7-DHC) to pre-vitamin D3 that is thermally isomerized to vitamin D3. In addition to free vitamin D3, it has been previously reported that esterified vitamin D3 is also found in the skin of rats irradiated with UVB. We found that a large fraction of the vitamin D3 precursor, 7-dehydrocholesterol is in the esterified form. Following UVB irradiation, vitamin D3 esters represent the majority of tissue vitamin D3, comprising approximately 80% in mice. Examination of vitamin D3 ester transport from skin in DBP-/- mice demonstrated that skin vitamin D3 ester content decreased only in the presence of DBP. No significant binding of vitamin D3 esters by serum was observed and no vitamin D3 esters were detectable in mouse serum after UVB treatment, indicating that the esters are hydrolyzed prior to transport into the circulation. The significance of vitamin D3 esters and their hydrolysis is the subject of current investigation.

Novel superagonist analogs of 2-methylene calcitriol: Design, molecular docking, synthesis and biological evaluation.

A new series of highly biologically active (20S,22R)-1α,25-dihydroxy-22-methyl-2-methylene-vitamin D3 analogs, possessing different side chains, have been efficiently prepared as potential agents for medical therapy. Design of these synthetic targets was based on the analysis of the literature data and molecular docking experiments. The synthetic strategy involved Sonogashira coupling of the known A-ring dienyne with the C,D-ring enol triflates, obtained from the corresponding Grundmann ketones. All synthesized vitamin D compounds were characterized by high in vitro potency and, moreover, they proved to be very calcemic in vivo exerting high activity on bone with particularly elevated intestinal calcium transport.

Toward Molecular Cooperation by De Novo Peptides.

Theoretical models of the chemical origins of life depend on self-replication or autocatalysis, processes that arise from molecular interactions, recruitment, and cooperation. Such models often lack details about the molecules and reactions involved, giving little guidance to those seeking to detect signs of interaction, recruitment, or cooperation in the laboratory. Here, we develop minimal mathematical models of reactions involving specific chemical entities: amino acids and their condensation reactions to form de novo peptides. Reactions between two amino acids form a dipeptide product, which enriches linearly in time; subsequent recruitment of such products to form longer peptides exhibit super-linear growth. Such recruitment can be reciprocated: a peptide contributes to and benefits from the formation of one or more other peptides; in this manner, peptides can cooperate and thereby exhibit autocatalytic or exponential growth. We have started to test these predictions by quantitative analysis of de novo peptide synthesis conducted by wet-dry cycling of a five-amino acid mixture over 21 days. Using high-performance liquid chromatography, we tracked abundance changes for >60 unique peptide species. Some species were highly transient, with the emergence of up to 17 new species and the extinction of nine species between samplings, while other species persisted across many cycles. Of the persisting species, most exhibited super-linear growth, a sign of recruitment anticipated by our models. This work shows how mathematical modeling and quantitative analysis of kinetic data can guide the search for prebiotic chemistries that have the potential to cooperate and replicate.

Synthesis and Biological Activity of 2,22-Dimethylene Analogues of 19-Norcalcitriol and Related Compounds.

Continuing our search for vitamin D analogues, we explored the modification of the steroidal side chain and inserted a methylene moiety in position C-22 together with either lengthening the side chain or introducing a ring at the terminal end. Our conformational studies confirmed that the presence of a methylene group attached to C-22 restricts the conformational flexibility of the side chain, which can result in changes in biological characteristics of a molecule. All synthesized 1α,25-dihydroxy-2,22-dimethylene-19-norvitamin D3 analogues proved equal to calcitriol in their ability to bind to the vitamin D receptor, and most of them exert significantly higher differentiation and transcriptional activity than calcitriol. The most active compounds were characterized by the presence of an elongated side chain or 26,27-dimethylene bridge. The synthetic strategy was based on the Wittig-Horner coupling of the known A-ring phosphine oxide with the corresponding Grundmann ketones prepared from a 20-epi-Inhoffen-Lythgoe diol derived from vitamin D2.