A series of bile acid derived 1,2- and 1,3-diamines as well as their platinum(II) complexes were designed and synthesized in hope to get a highly cytotoxic compound by the combination of two ...bioactive moieties. All complexes obtained were subjected to cytotoxicity assays in vitro and some hybrid molecules showed an expected activity.
Rotamers are stereoisomers produced by rotation (twisting) about σ bonds and are often rapidly interconverting at room temperature. Xylitol-massively produced sweetener-(2
,3
,4
...)-pentane-1,2,3,4,5-pentol) forms rotamers from the linear conformer by rotation of a xylitol fragment around the C2-C3 bond (rotamer 1) or the C3-C4 bond (rotamer 2). The rotamers form two distinguishable structures. Small differences in geometry of rotamers of the main carbon chain were confirmed by theoretical calculations; however, they were beyond the capabilities of the X-ray powder diffraction technique due to the almost identical unit cell parameters. In the case of rotamers of similar compounds, the rotations occurred mostly within hydroxyl groups likewise rotations in L-arabitol and D-arabitol, which are discussed in this work. Our results, supported by theoretical calculations, showed that energetic differences are slightly higher for rotamers with rotations within hydroxyl groups instead of a carbon chain.
The biologically active metabolite of vitamin D3 - calcitriol – is a hormone involved in the regulation of calcium-phosphate homeostasis, immunological processes and cell differentiation, being ...therefore essential for the proper functioning of the human body. This suggests many applications of this steroid in the treatment of diseases such as rickets, psoriasis and some cancers. Unfortunately, using therapeutic doses of calcitriol is associated with high concentrations of this compound which causes hypercalcemia. For this reason, new calcitriol analogs are constantly sought, devoid of calcemic effects but maintaining its beneficial properties. In this study, we present the synthesis of vitamin D derivatives characterized by an enlarged (seven-membered) ring D. Preparation of the designed vitamin D compounds required separate syntheses of crucial building blocks (C/D-rings fragments with side chain and rings A) which were combined by different methods, including Wittig-Horner reaction and Suzuki coupling. Biological activities of the target vitamin D analogs were assessed both in vitro and in vivo, demonstrating their significant potency compared to the natural hormone. Furthermore, the successful crystallization of these compounds with the vitamin D receptor (VDR) enabled us to investigate additional molecular interactions with this protein.
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•First total synthesis of vitamin D3 analogs with 7-membered ring D.•X-ray crystal structures of zVDR LBD complexes of all synthesized analogs.•In vitro activity of all analogs in lung, breast and leukemia cell lines.•Synthesized analogs are active in stimulating calcium homeostasis in vivo.
CYP11A1 and CYP27A1 hydroxylate tachysterol3, a photoproduct of previtamin D3, producing 20S‐hydroxytachysterol3 20S(OH)T3 and 25(OH)T3, respectively. Both metabolites were detected in the human ...epidermis and serum. Tachysterol3 was also detected in human serum at a concentration of 7.3 ± 2.5 ng/ml. 20S(OH)T3 and 25(OH)T3 inhibited the proliferation of epidermal keratinocytes and dermal fibroblasts and stimulated the expression of differentiation and anti‐oxidative genes in keratinocytes in a similar manner to 1,25‐dihydroxyvitamin D3 1,25(OH)2D3. They acted on the vitamin D receptor (VDR) as demonstrated by image flow cytometry and the translocation of VDR coupled GFP from the cytoplasm to the nucleus of melanoma cells, as well as by the stimulation of CYP24A1 expression. Functional studies using a human aryl hydrocarbon receptor (AhR) reporter assay system revealed marked activation of AhR by 20S(OH)T3, a smaller effect by 25(OH)T3, and a minimal effect for their precursor, tachysterol3. Tachysterol3 hydroxyderivatives showed high‐affinity binding to the ligan‐binding domain (LBD) of the liver X receptor (LXR) α and β, and the peroxisome proliferator‐activated receptor γ (PPARγ) in LanthaScreen TR‐FRET coactivator assays. Molecular docking using crystal structures of the LBDs of VDR, AhR, LXRs, and PPARγ revealed high docking scores for 20S(OH)T3 and 25(OH)T3, comparable to their natural ligands. The scores for the non‐genomic‐binding site of the VDR were very low indicating a lack of interaction with tachysterol3 ligands. Our identification of endogenous production of 20S(OH)T3 and 25(OH)T3 that are biologically active and interact with VDR, AhR, LXRs, and PPARγ, provides a new understanding of the biological function of tachysterol3.
The biologically active metabolite of vitamin D
- calcitriol - is a hormone involved in the regulation of calcium-phosphate homeostasis, immunological processes and cell differentiation, being ...therefore essential for the proper functioning of the human body. This suggests many applications of this steroid in the treatment of diseases such as rickets, psoriasis and some cancers. Unfortunately, using therapeutic doses of calcitriol is associated with high concentrations of this compound which causes hypercalcemia. For this reason, new calcitriol analogs are constantly sought, devoid of calcemic effects but maintaining its beneficial properties. In this study, we present the synthesis of vitamin D derivatives characterized by an enlarged (seven-membered) ring D. Preparation of the designed vitamin D compounds required separate syntheses of crucial building blocks (C/D-rings fragments with side chain and rings A) which were combined by different methods, including Wittig-Horner reaction and Suzuki coupling. Biological activities of the target vitamin D analogs were assessed both in vitro and in vivo, demonstrating their significant potency compared to the natural hormone. Furthermore, the successful crystallization of these compounds with the vitamin D receptor (VDR) enabled us to investigate additional molecular interactions with this protein.
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.
Continuing our structure-activity studies on the vitamin D analogs with the altered intercyclic seco-B-ring fragment, we designed compounds possessing dienyne system conjugated with the benzene D ...ring. Analysis of the literature data and the docking experiments seemed to indicate that the target compounds could mimic the ligands with a good affinity to the vitamin D receptor (VDR). Multi-step synthesis of the C/D-ring building block of the tetralone structure was achieved and its enol triflate was coupled with the known A-ring fragments, possessing conjugated enyne moiety, using Sonogashira protocol. The structures of the final products were confirmed by NMR, UV and mass spectroscopy. Their binding affinities for the full-length human VDR were determined and it was established that compound substituted at C-2 with exomethylene group showed significant binding to the receptor. This analog was also able to induce monocytic differentiation of HL-60 cells.
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•A-Ring fragment’s synthesis started from cyclohexanone derived from quinic acid.•19-Norcalcitriol analogs with pegylated 2-alkylidene groups were synthesized.•2-Alkylidene chain is ...terminated by hydroxyl or 2-(pyridin-2′-yl)ethylamino group.•The affinities of the synthesized 19-norcalcitriol analogs to VDR were assessed.
The results presented in this paper constitute an extension of our synthetic efforts focused on 19-norvitamin D compounds possessing elongated 2-alkylidene substituents. Based on our previous results, molecular modeling studies, and docking experiments, we selected a novel 19-norcalcitriol analog with long chain at C-2 containing several ether moieties and terminated by 2-(pyridin-2′-yl)ethylamino fragment. It was expected that such structural modification might allow binding of transition metal by the ligand, increase solubility of the formed complexes as well as improve their affinity to the VDR. For comparison, a 19-norcalcitriol analog was also obtained with the terminal hydroxyl group at its pegylated 2-alkylidene substituent. The synthesis of the target vitamin D compounds described in this work was performed using the Wittig-Horner approach. The respective A-ring phosphine oxide was obtained starting from the D-(-)-quinic acid and then coupled with the known Grundmann ketone.
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•Starting from the natural compounds synthesis of the building blocks was achieved.•19-Norcalcitriol analog with elongated side chain obtained by Wittig-Horner coupling.•The side ...chain of the synthesized analog can protrude from the VDR binding pocket.
Pronounced biological potency of 19-norvitamin D compounds as well as interesting biological action of the vitamin D analogs possessing elongated side chains encouraged us to expand the scope of our structure-activity studies to encompass such modifications of the 1α,25-(OH)2D3 (calcitriol) molecule. The aim of our studies was the synthesis of calcitriol analog, designed on the basis of results of molecular modeling and docking experiments, and characterized by a presence of a long, nitrogen-containing substituent attached to carbon 26, and an exomethylene moiety transferred from C-10 to C-2. The convergent synthesis of such 19-norcalcitriol compound, described in this communication, consisted of the preparation and combining four building blocks. The crucial point of the synthesis, coupling of the known A-ring phosphine oxide and the synthesized Grundmann ketone analog, was achieved using Wittig-Horner protocol. It provided the protected analog of 1α,25-dihydroxy-2-methylene-19-norvitamin D3 which was further transformed into the target compound.
Two new square planar ONNO nickel(II) complexes C2_core and C3_core have been synthesized and characterized by single crystal X‐ray diffraction, NMR spectroscopy, thermogravimetry, and DFT ...calculations. The experimental results revealed the effect of the length of diamine bridge in the ligand on the behavior of the studied complexes in the reaction with N‐heterocyclic aromatic amines, while DFT calculations provided a basis for the rationalization of this observation. The complex with propylenediamine bridge (C3_core) readily reacts with pyridine and its derivatives to form high‐spin (paramagnetic) complexes with octahedral geometry as characterized by X‐ray diffraction; electron‐donating substituents on the pyridine ring facilitate the coordination of axial ligands. In contrast, the complex with ethylenediamine bridge (C2_core) does not undergo such a reaction because of the high deformation energy of the core required for the formation of C2_Py complex.
C2 or C3? Comparison of two synthesized and characterized square planar Ni(II) complexes showed that the length of the diamine bridge in the equatorial ligand plays a crucial role in the reaction with N‐heterocyclic aromatic amines. Only complex with propylenediamine bridge attaches pyridine derivatives switching from square planar low‐spin to octahedral high‐spin structure.
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