RESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low density lipoprotein receptor (LDLR). Anti-PCSK9 agents have been approved for the treatment of hypercholesterolemia. We recently discovered a series of small-molecule PCSK9 modulators that contains a relatively small pharmacophore of 2,3'-diindolylmethane with molecular weights around only 250. These molecules can significantly lower the amount of PCSK9 protein in a cell-based phenotypic assay. Our SAR studies yielded compound 16 with a IC50-value of 200â¯nM. No obvious cytotoxicity was observed at concentrations below 50⯵M.
Assuntos
Descoberta de Drogas , Hipercolesterolemia/tratamento farmacológico , Indóis/farmacologia , Inibidores de PCSK9 , Bibliotecas de Moléculas Pequenas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Hipercolesterolemia/metabolismo , Indóis/síntese química , Indóis/química , Estrutura Molecular , Pró-Proteína Convertase 9/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
An unsymmetrical bimetallic catalyst, (CF3/SO2)FI2-Ni2, having a CF3-functionalized phenoxyiminato Ni(II) center, which produces linear high-Mw polyolefin (CF3/Ni) joined to an adjacent SO2-functionalized phenoxyiminato Ni(II) center, which produces highly branched low-Mw polyolefin (SO2/Ni), was synthesized and fully characterized. In ethylene homopolymerizations, (CF3/SO2)FI2-Ni2 affords monomodal (D = 1.7), highly, long-chain branched (69 branches/1000 C) polyethylenes with Mw = 24 kg/mol. In contrast, bimetallic (CF3)FI2-Ni2 and (SO2)FI2-Ni2 produce high-Mw (25 kg/mol) exclusively methyl-branched (40 branches/1000 C) and low-Mw (4.5 kg/mol) highly branched (105 branches/1000 C) polyethylenes, respectively, while tandem monometallic (CF3)FI-Ni + (SO2)FI-Ni catalyst mixtures yield a bimodal polyolefin mixture (D = 6.4).
RESUMO
Recent studies suggest that arylhydrocarbon receptor (AhR) may be a target for a number of diseases. Natural product malassezin is a AhR agonist with an interesting 2,3'-diindolylmethane skeleton. We have prepared a series of analogues of natural product malassezin using our recently developed method and tested the activity of these analogues against AhR in a cell-based assay. We found that a methyl substituent at 1'-N can significantly increase the activity and the 2-formyl group is not critical for some diindolylmethanes.
Assuntos
Indóis/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Various diindolylmethanes were prepared from propargylic ethers and substituted indoles via a platinum-catalyzed tandem indole annulation/arylation cascade. The resulting diindolylmethanes could be converted to natural product malassezin by formylation or indolo[3,2-b]carbazoles by cyclization.
Assuntos
Alcinos/química , Carbazóis/síntese química , Éteres/química , Indóis/síntese química , Platina/química , Catálise , Ciclização , Indóis/química , Estrutura MolecularRESUMO
Transition metal-catalyzed acyloxy migration of propargylic esters offers versatile entries to allene and vinyl carbene intermediates for various fascinating subsequent transformations. Most π-acidic metals (e.g. gold and platinum) are capable of facilitating these acyloxy migration events. However, very few of these processes involve redox chemistry, which are well-known for most other transition metals such as rhodium. The coupling of acyloxy migration of propargylic esters with oxidative addition, migratory insertion, and reductive elimination may lead to ample new opportunities for the design of new reactions. This tutorial review summarizes recent developments in Rh-catalyzed 1,3- and 1,2-acyloxy migration of propargylic esters in a number of cycloaddition reactions. Related Au- and Pt-catalyzed cycloadditions involving acyloxy migration are also discussed.
Assuntos
Ródio/química , Catálise , Reação de Cicloadição , Ésteres , Metano/análogos & derivados , Metano/química , EstereoisomerismoRESUMO
We have developed two different types of tandem reactions for the synthesis of highly functionalized cyclohexenones from cyclopropyl substituted propargyl esters. Both reactions were initiated by rhodium-catalyzed Saucy-Marbet 1,3-acyloxy migration. The resulting cyclopropyl substituted allenes derived from acyloxy migration then underwent [5 + 1] cycloaddition with CO. The acyloxy group not only eased the access to allene intermediates but also provided a handle for further selective functionalizations.
Assuntos
Ciclopropanos/química , Ésteres/química , Cetonas/síntese química , Ródio/química , Monóxido de Carbono/química , Catálise , Ciclização , Cetonas/química , Estrutura MolecularRESUMO
Functionalized cyclopentenones were synthesized by a Rh-catalyzed carbonylation of 3-acyloxy-1,4-enynes, derived from alkynes and α,ß-unsaturated aldehydes. The reaction involved a Saucy-Marbet 1,3-acyloxy migration of propargyl esters and a [4 + 1] cycloaddition of the resulting acyloxy substituted vinylallene with CO.
Assuntos
Alcinos/química , Ciclopentanos/síntese química , Ródio/química , Catálise , Técnicas de Química Combinatória , Ciclização , Ciclopentanos/química , Estrutura Molecular , EstereoisomerismoRESUMO
A new type of rhodium-catalyzed [5 + 2] cycloaddition was developed for the synthesis of seven-membered rings with diverse functionalities. The ring formation was accompanied by a 1,2-acyloxy migration event. The five- and two-carbon components of the cycloaddition are 3-acyloxy-1,4-enynes (ACEs) and alkynes, respectively. Cationic rhodium(I) catalysts worked most efficiently for the intramolecular cycloaddition, while only neutral rhodium(I) complexes could facilitate the intermolecular reaction. In both cases, electron-poor phosphite or phosphine ligands often improved the efficiency of the cycloadditions. The scope of ACEs and alkynes was investigated in both the intra- and intermolecular reactions. The resulting seven-membered-ring products have three double bonds that could be selectively functionalized.
Assuntos
Alcinos/química , Cicloparafinas/síntese química , Ródio/química , Catálise , Ciclização , Cicloparafinas/química , Estrutura MolecularRESUMO
Rholling in the bicycles: a rhodium(I)-catalyzed cycloisomerization for the synthesis of bicyclic compounds containing a cycloheptatriene ring from linear alkenynes (see scheme; cod=1,5-cyclooctadiene) is proposed to proceed through 1,2-acyloxy migration, 6 π electrocyclization, migratory insertion, and reductive elimination. The overall process can be viewed as a novel intramolecular [5+2] cycloaddition with concomitant 1,2-acyloxy migration.