RESUMO
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
The naphterpins and marinones are naphthoquinone meroterpenoids with an unusual aromatic oxidation pattern that is biosynthesized from 1,3,6,8-tetrahydroxynaphthalene (THN). We propose that cryptic halogenation of THN derivatives by vanadium-dependent chloroperoxidase (VCPO) enzymes is key to this biosynthetic pathway, despite the absence of chlorine in these natural products. This speculation inspired a total synthesis to mimic the naphterpin/marinone biosynthetic pathway. In validation of this biogenetic hypothesis, two VCPOs were discovered that interconvert several of the proposed biosynthetic intermediates.
Assuntos
Produtos Biológicos/metabolismo , Naftoquinonas/metabolismo , Terpenos/metabolismo , Produtos Biológicos/química , Biomimética , Cloreto Peroxidase/metabolismo , Ciclização , Halogenação , Naftóis/química , Naftóis/metabolismo , Naftoquinonas/química , Oxirredução , Reprodutibilidade dos Testes , Terpenos/químicaRESUMO
The onset of new multidrug-resistant strains of bacteria demands continuous development of antibacterial agents with new chemical scaffolds and mechanisms of action. We present the first structure-activity relationship (SAR) study of 16 derivatives of a structurally novel antibiotic merochlorinâ A that were designed using a biosynthetic blueprint. Our lead compounds are active against several Gram-positive bacteria such as Staphylococcus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and Bacillus subtilis, inhibit intracellular growth of Mycobacterium bovis, and are relatively nontoxic to human cell lines. Furthermore, derivative 12 c {(±)-(3aR,4S,5R,10bS)-5-bromo-7,9-dimethoxy-4-methyl-4-(4-methylpent-3-en-1-yl)-2-(propan-2-ylidene)-1,2,3,3a,4,5-hexahydro-6H-5,10b-methanobenzo[e]azulene-6,11-dione} was found to inhibit the growth of Bacillus Calmette-Guérin (BCG)-infected cells at concentrations similar to rifampicin. These results outperform the natural product, underscoring the potential of merochlorin analogues as a new class of antibiotics.
Assuntos
Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , Eritrócitos/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Sesterterpenos/farmacologia , Animais , Antibacterianos/biossíntese , Antibacterianos/química , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Eritrócitos/microbiologia , Cavalos , Testes de Sensibilidade Microbiana , Conformação Molecular , Sesterterpenos/biossíntese , Sesterterpenos/química , 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.