RESUMO
Since the discovery of vitamin D a century ago, a great number of metabolites, analogs, hybrids and nonsteroidal VDR ligands have been developed. An enormous effort has been made to synthesize compounds which present beneficial properties while attaining lower calcium serum levels than calcitriol. This structural review covers VDR ligands published to date.
Assuntos
Receptores de Calcitriol , Vitamina D , Receptores de Calcitriol/metabolismo , Ligantes , Vitaminas , CalcitriolRESUMO
The toxic calcemic effects of the natural hormone 1α,25-dihydroxyvitamin D3 (1,25D3, 1,25-dihydroxycholecalciferol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D3 that lack the C-ring and possess an m-phenylene ring that replaces the natural D-ring. The new analogues (3a, 3b) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system. Both compounds were synthesized by the Pd-catalyzed tandem cyclization/cross coupling approach starting from alkyne 6 and diphenol 8. Key steps include a stereoselective Cu-assisted addition of a Grignard reagent to an aromatic alkyne and a Takai olefination of an aromatic aldehyde. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D3. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.
Assuntos
Calcitriol , Receptores de Calcitriol , Aldeídos , Alcinos/farmacologia , Calcitriol/farmacologia , Carbono , Hormônios , Paládio/química , Vitamina D/análogos & derivadosRESUMO
Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1α,25-dihydroxyvitamin D3 analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility. The triene system was constructed by a Pd0 -mediated cyclization/Suzuki-Miyaura cross-coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester-Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)-1α,25-dihydroxy-17,20-dien-24-homo-21-nor-vitamin D3 bound to binding domain of the vitamin D receptor, provide information concerning side-chain conformational requirements for biological activity.
Assuntos
Calcitriol , Vitamina D , Ligantes , Conformação Molecular , Vitamina D/análogos & derivadosRESUMO
The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73-93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (µ), chemical hardness (η), and electrophilicity (ω) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29-31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/síntese química , Inibidores do Fator Xa/farmacologia , Fator Xa/química , Quinolinas/química , Triazóis/química , Compostos de Anilina/síntese química , Compostos de Anilina/química , Azidas/síntese química , Azidas/química , Testes de Coagulação Sanguínea , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Fator Xa/metabolismo , Inibidores do Fator Xa/química , Humanos , Concentração Inibidora 50 , Ligantes , Micro-Ondas , Simulação de Acoplamento Molecular , Quinolinas/síntese química , Triazóis/síntese químicaRESUMO
For many individuals, in particular during winter, supplementation with the secosteroid vitamin D3 is essential for the prevention of bone disorders, muscle weakness, autoimmune diseases, and possibly also different types of cancer. Vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as potent agonist of the transcription factor vitamin D receptor (VDR). Thus, vitamin D directly affects chromatin structure and gene regulation at thousands of genomic loci, i.e., the epigenome and transcriptome of its target tissues. Modifications of 1,25(OH)2D3 at its side-chain, A-ring, triene system, or C-ring, alone and in combination, as well as nonsteroidal mimics provided numerous potent VDR agonists and some antagonists. The nearly 150 crystal structures of VDR's ligand-binding domain with various vitamin D compounds allow a detailed molecular understanding of their action. This review discusses the most important vitamin D analogs presented during the past 10 years and molecular insight derived from new structural information on the VDR protein.
Assuntos
Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Animais , Calcifediol/análogos & derivados , Calcifediol/metabolismo , Calcitriol/análogos & derivados , Calcitriol/metabolismo , Humanos , Estrutura Secundária de Proteína , Estrutura Terciária de ProteínaRESUMO
As part of our program on synthesis of labeled vitamin D metabolites and analogs, we describe here an efficient and versatile synthetic approach to 28,28,28-trideutero- 25-hydroxydihydrotachysterol2 where isotopic labeling was incorporated stereoselectively in the last step of the synthesis. This deuterated compound will allow the study this analog in vitro or in vivo and to measure AT10-like compounds in serum by LC-MS/MS.
Assuntos
Di-Hidrotaquisterol/análogos & derivados , Di-Hidrotaquisterol/análise , Di-Hidrotaquisterol/química , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Deutério/química , Di-Hidrotaquisterol/síntese química , Coloração e Rotulagem , Vitamina D/químicaRESUMO
Herein, we describe a synthetic strategy to access 1α,25-dihydroxyvitamin D3 (calcitriol) analogs with natural or unnatural configuration at C20 and unsaturation at the D-ring. The synthetic approach is exemplified by the synthesis of two potent analogs, namely 1α,25-dihydroxy-16-en-23-yne-vitamin D3 and 1α,25-dihydroxy-20-epi-24a-homo-26,27-dimethyl-vitamin D3. A key feature of the synthetic strategy is the generation of an unnatural configuration at C20 by a catalytic asymmetric reduction of an α,ß,γ,δ-unsaturated ester with the CuH species in a micellar system.
Assuntos
Calcitriol/análogos & derivados , Calcitriol/síntese química , EstereoisomerismoRESUMO
We report the design, synthesis, biological evaluation, and structural analysis of a new class of vitamin D analogues that possess an aromatic m-phenylene D-ring and an alkyl chain replacing the C-ring. A key feature of the synthetic strategy is a stereoselective Pd-catalyzed construction of the triene system in aqueous medium that allows the rapid preparation of small amounts of VDR ligands for biological screening. Analogues with the shorter (2a) and longer (2d, 2e) side chains attached to the triene system have no calcemic activity. Compound 2a binds to VDR with the same order of magnitude than calcipotriol and oxacalcitriol. It also reduces proliferation in normal and tumor cells similarly to the natural hormone 1α,25-dihydroxyvitamin D3, calcipotriol, and oxacalcitriol, suggesting preclinical studies related to hyperproliferative disorders such as psoriasis and cancer.
Assuntos
Desenho de Fármacos , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/farmacologia , Receptores de Calcitriol/agonistas , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Hidrocarbonetos Aromáticos/metabolismo , Camundongos , Modelos Moleculares , Conformação Molecular , Receptores de Calcitriol/metabolismoRESUMO
A convergent synthesis of side-chain locked vitamin D analogs 3 and 4, which bind strongly in silico to the vitamin D receptor (VDR), is described. The synthetic approach features an SN2'- syn displacement of carbamates by cuprates to set the challenging quaternary stereogenic center at C17 and a Pd-catalyzed construction of the triene system in the presence of a diyne moiety.
RESUMO
A convergent approach to 25S,26-dihydroxyvitamin D3 (1) has been developed in our laboratories. The A-ring and the CD-fragment are constructed from ergocalciferol and Inhoffen-Lythgoe diol, respectively. The triene system is assembled by a Wittig-Horner coupling. With this convergent synthesis, a novel hydroxylated vitamin D metabolite in our laboratory is available for biological testing.
Assuntos
Vitamina D/análogos & derivados , Catálise , Estrutura Molecular , Osmio/química , Estereoisomerismo , Vitamina D/síntese químicaRESUMO
We describe an efficient convergent synthesis of vitamin D3 metabolites and analogues. The synthetic strategy relies on a tandem Pd-catalyzed A-ring closure and Suzuki-Miyaura coupling to the CD-side chain component to set directly the vitamin D triene system under protic conditions. This strategy enables rapid access to vitamin D3 and 3-epi-vitamin D3 metabolites and analogues modified at the side chain for biological evaluation and structural and metabolic studies.
Assuntos
Colecalciferol/análogos & derivados , Colecalciferol/síntese química , Paládio/química , Catálise , Colecalciferol/química , Estrutura Molecular , Solventes/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Herein, we describe a versatile and efficient total synthesis of 1α,25-dihydroxyvitamin D3 (calcitriol). The synthetic strategy relies on an unprecedented Si-assisted SN2'-syn displacement of carbamates by cuprates to set the challenging pivotal quaternary methyl group at the fused-ring junction of the CD-trans-hydrindane core. Other key transformations involve the catalytic asymmetric reduction of an α,ß,γ,δ-unsaturated ester with CuH to generate the natural steroidal configuration at C20 and a Pauson-Khand cyclization to form the CD-ring skeleton. This strategy enables the syntheses of novel analogs for structure-function studies and drug development.
RESUMO
A new approach to 19-nor-A-ring phosphine oxide 5 together with a convergent synthesis of the vitamin D3 analogue 1α,25-dihydroxy-19-norvitamin D3 (3) have been developed. The 19-nor-A-ring is constructed from (S)-carvone. The triene system is assembled by a Wittig-Horner coupling.
Assuntos
Calcitriol/síntese química , Técnicas de Química Sintética/métodos , Fosfinas/química , Vitaminas/síntese química , Calcitriol/análogos & derivados , Monoterpenos Cicloexânicos , Monoterpenos/síntese química , Monoterpenos/química , Óxidos/síntese química , Óxidos/química , Fosfinas/síntese química , Vitaminas/químicaRESUMO
INTRODUCTION: Vitamin D3 activates via its hormonal form 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), the transcription factor vitamin D receptor (VDR). VDR is expressed in most human tissues and has more than 1,000 target genes. Thus, 1α,25(OH)2D3 and its synthetic analogs have a broad physiological impact. The crystal structures of the VDR ligand-binding domain (LBD), and its various ligands, allows further the understanding of the receptor's molecular actions. Areas covered: We discuss the most important novel VDR ligands and the further insight derived from new structural information on VDR. Expert opinion: There is an increasing appreciation of the impact of vitamin D and its receptor VDR not only in bone biology, but also for metabolic diseases, immunological disorders, and cancer. Detailed structural analysis of the interaction of additional novel ligands with VDR highlight helices 6 and 7 of the LBD as being most critical for stabilizing the receptor for an efficient interaction with co-activator proteins, i.e. for efficient agonistic action. This permits the design of even more effective VDR agonists. In addition, chemists took more liberty in replacing major parts of the 1α,25(OH)2D3 molecule, such as the A- and CD-rings or the side chain, with significantly different structures, such as carboranes, and still obtained functional VDR agonists.
Assuntos
Calcitriol/análogos & derivados , Desenho de Fármacos , Receptores de Calcitriol/agonistas , Animais , Calcitriol/metabolismo , Calcitriol/farmacologia , Colecalciferol/metabolismo , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/patologia , Ligantes , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/patologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Patentes como Assunto , Receptores de Calcitriol/metabolismoRESUMO
A mild convergent synthesis of 1ß,25-dihydroxyvitamin D3 (3a), a metabolite of vitamin D3, and its C26,27-hexadeuterated derivative (3b) are described. The A-ring and the CD-fragments are constructed from (R)-carvone and Inhoffen-Lythgoe diol, respectively. The triene system is assembled by a Pd(0)-catalyzed process, which involves an enol-triflate (A-ring fragment) and an alkenyl boronate (CD-side chain fragment). Deuterium labeling is introduced at the last step of the synthesis.
Assuntos
Calcitriol/síntese química , Aldeídos/química , Calcitriol/análogos & derivados , Calcitriol/química , Catálise , Monoterpenos Cicloexânicos , Desenho de Fármacos , Estrutura Molecular , Monoterpenos/química , Paládio/química , Ligação Proteica , Estereoisomerismo , Vitamina D/análogos & derivados , Vitamina D/síntese química , Vitamina D/químicaRESUMO
The vitamin D nuclear receptor (VDR) is a potential target for cancer therapy. It is expressed in many tumors and its ligand shows anticancer actions. To combine these properties with the application of boron neutron capture therapy (BNCT), we design and synthesize a potent VDR agonist based on the skeleton of the hormone 1α,25-dihydroxyvitamin D3 (1,25D) and an o-carborane (dicarba-o-closo-1,2-dodecaborane) at the end of its side chain. The present ligand is the first secosteroidal analog with the carborane unit that efficiently binds to VDR and functions as an agonist with 1,25D-like potency in transcriptional assay on vitamin D target genes. Moreover it exhibits similar antiproliferative and pro-differentiating activities but is significantly less hypercalcemic than 1,25D. The crystal structure of its complex with VDR ligand binding domain reveals its binding mechanism involving boron-mediated dihydrogen bonds that mimic vitamin D hydroxyl interactions. In addition to the therapeutic interest, this study establishes the basis for the design of new unconventional vitamin D analogs containing carborane moieties for specific molecular recognition, and drug research and development.
RESUMO
The nucleophilic addition (A(N)) / intramolecular aza-Michael reaction (IMAMR) process on Ellman's tert-butylsulfinyl imines, bearing a Michael acceptor in the ortho position, is studied. This reaction affords 1,3-disubstituted isoindolines with a wide range of substituents in good yields and diastereoselectivities. Interestingly, careful choice of the base for the aza-Michael step allows either the cis or the trans diastereoisomers to be exclusively obtained. This stereodivergent cyclization has enabled the synthesis of C2-symmetric bisacetate-substituted isoindolines. In addition, bisacetate isoindolines bearing two well-differentiated ester moieties are also noteworthy because they may allow for the orthogonal synthesis of ß,ß'-dipeptides using a single nitrogen atom as a linchpin.
RESUMO
Enantiomerically pure fluorinated isoindoline and dihydroisoquinoline scaffolds have been prepared through a diastereoselective addition of fluorinated nucleophiles to Ellman's N-(tert-butanesulfinyl)imines followed by a sequence of Sonogashira cross-coupling/gold(I)-catalyzed cycloisomerization of the corresponding carbamate. A more favored 5-exo-dig mechanism was observed mainly due to an electronic effect of the fluorinated group.
Assuntos
Carbamatos/química , Ouro/química , Hidrocarbonetos Fluorados/síntese química , Isoindóis/síntese química , Isoquinolinas/síntese química , Aminas/química , Catálise , Hidrocarbonetos Fluorados/química , Isoindóis/química , Isoquinolinas/química , Estrutura Molecular , EstereoisomerismoRESUMO
A gold-catalyzed tandem intramolecular hydroamination-formal aza-Diels-Alder reaction of propargylic amino esters is described. The overall process leads to the formation of a tetracyclic framework as a single diastereoisomer, with the creation of four bonds and five stereocenters.
RESUMO
Aromatic tert-butylsulfinyl ketimines bearing a suitable Michael acceptor at the ortho position readily undergo an intramolecular conjugate addition achieving indanone derivatives in good yields and complete diastereoselectivity.