RESUMO
The cobalt(II) complexes of D2-symmetric chiral porphyrins, such as 3,5-Di(t)Bu-ChenPhyrin P5, can catalyze asymmetric olefin aziridination with diphenylphosphoryl azide (DPPA) as a nitrene source. Acceptable asymmetric inductions were observed for the [Co(P5)]-based catalytic system, forming the desired N-phosphorus-substituted aziridines in moderate to high yields and good enantioselectivities.
Assuntos
Alcenos/química , Azidas/química , Aziridinas/síntese química , Cobalto/química , Compostos Organometálicos/química , Porfirinas/química , Aziridinas/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
The ALDH2*2 gene encoding the inactive variant form of mitochondrial aldehyde dehydrogenase (ALDH2) protects nearly all carriers of this gene from alcoholism. Inhibition of ALDH2 has hence become a possible strategy to treat alcoholism. The natural product 7-O-glucosyl-4'-hydroxyisoflavone (daidzin), isolated from the kudzu vine ( Peruraria lobata), is a specific inhibitor of ALDH2 and suppresses ethanol consumption. Daidzin is the active principle in a herbal remedy for "alcohol addiction" and provides a lead for the design of improved ALDH2. The structure of daidzin/ALDH2 in complex at 2.4 A resolution shows the isoflavone moiety of daidzin binding close to the aldehyde substrate-binding site in a hydrophobic cleft and the glucosyl function binding to a hydrophobic patch immediately outside the isoflavone-binding pocket. These observations provide an explanation for both the specificity and affinity of daidzin (IC50 =80 nM) and the affinity of analogues with different substituents at the glucosyl position.
Assuntos
Alcoolismo/enzimologia , Aldeído Desidrogenase/antagonistas & inibidores , Comportamento Aditivo/enzimologia , Isoflavonas/química , Isoflavonas/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Aldeído Desidrogenase/metabolismo , Família Aldeído Desidrogenase 1 , Aldeído-Desidrogenase Mitocondrial , Animais , Sítios de Ligação , Cricetinae , Cristalografia por Raios X , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estrutura Molecular , Retinal Desidrogenase , Relação Estrutura-AtividadeRESUMO
Diporphyrins can be efficiently synthesized from bromoporphyrin precursors via palladium-catalyzed C-O bond formation. The synthetic methodology is general and can be applied to various diols, forming a series of homo-diporphyrins containing different types of spacers in high to excellent yields. Chiral diporphyrins can be readily constructed through the use of optically active diols. A similar strategy allows access to hetero-diporphyrins and triporphyrins, including free-base and metalloporphyrin hetero dimers.
Assuntos
Paládio/química , Porfirinas/síntese química , Catálise , Estrutura MolecularRESUMO
An efficient five step synthesis of benzamide riboside (BR) amenable for a large scale synthesis has been developed. It allows for extensive pre-clinical studies of BR as a potential anticancer agent.
Assuntos
Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , IMP Desidrogenase/antagonistas & inibidores , Nucleosídeos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Nicotinamida-Nucleotídeo Adenililtransferase/química , Nucleosídeos/biossíntese , Nucleosídeos/farmacologiaRESUMO
Cobalt, supported by porphyrin ligands, is capable of catalyzing intermolecular nitrene insertion of sp(3) C-H bonds with bromamine-T as the nitrene source, forming the desired tosyl-protected amines with NaBr as the by-product.
Assuntos
Aminas/síntese química , Cobalto/química , Iminas/química , Compostos Organometálicos/química , Porfirinas/química , Sulfonamidas/química , Aminação , Aminas/química , Catálise , Técnicas de Química Combinatória , Ligantes , Estrutura Molecular , EstereoisomerismoRESUMO
A procedure was developed for the preparation of beta-monobromo-tetraphenylporphyrin (BrTPP) in a greatly improved yield from the selective bromination of tetraphenylporphyrin (TPP) by NBS. BrTPP was successfully employed as a versatile synthon for convenient synthesis of a wide range of beta-monofunctionalized porphyrins with various heteroatom functionalities via palladium-mediated carbon-heteroatom bond formations. Examples include beta-amino, -amido, -oxo, and -mercaptoporphyrins from reactions with amines, amides, alcohols, and thiols, respectively. Applying the synthetic approach to chiral amides, beta-chiral porphyrins were effectively constructed.
Assuntos
Carbono/química , Paládio/química , Porfirinas/síntese química , Álcoois/química , Amidas/química , Aminas/química , Catálise , Halogenação , Modelos Químicos , Estereoisomerismo , Compostos de Sulfidrila/químicaRESUMO
The chemical synthesis of 4-phenoxybenzamide adenine dinucleotide (3), a NAD analogue which mimics isoniazid-NAD adduct and inhibits Mycobacterium tuberculosis NAD-dependent enoyl-ACP reductase (InhA), is reported. The 4-phenoxy benzamide riboside (1) has been prepared as a key intermediate, converted into its 5'-mononucleotide (2), and coupled with AMP imidazolide to give the desired NAD analogue 3. It inhibits InhA with IC50 = 27 microM.
Assuntos
Nucleotídeos de Adenina/síntese química , Nucleotídeos de Adenina/farmacologia , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Mycobacterium tuberculosis/enzimologia , NAD/análogos & derivados , Nucleotídeos de Adenina/química , Modelos Moleculares , Estrutura Molecular , NAD/química , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A new catalytic aziridination system that consists of cobalt(II) tetraphenylporphyrin [Co(TPP)] as the catalyst and diphenylphosphoryl azide (DPPA) as the nitrene source has been developed. The cobalt-based catalytic system allows direct synthesis of N-phosphorus-substituted aziridines from alkenes with dinitrogen as the byproduct. Cobalt ion seems essential to the catalytic aziridination with DPPA as no or only trace amounts of the desired products were observed with other metal complexes of tetraphenylporphyrin.
RESUMO
[reaction: see text]. Cobalt porphyrins are capable of catalyzing the aziridination of alkenes with bromamine-T as the nitrene source. Among cobalt complexes of different porphyrins, Co(TDClPP) is an effective catalyst that can aziridinate a wide variety of alkenes. The catalytic system can operate at room temperature in a one-pot fashion with alkenes as limiting reagents, forming the desired N-sulfonylated aziridine derivatives in high to excellent yields with NaBr as the byproduct.
RESUMO
A family of new meso-arylsulfanyl- and alkylsulfanyl-substituted porphyrins were efficiently synthesized from direct reactions of meso-brominated porphyrins with thiols via palladium-mediated C-S bond formation. The catalytic method can be performed under mild conditions with both mono- and bis-substituted meso-bromoporphyrins as well as their zinc complexes and is suitable for different types of thiols. With the use of selenols, meso-seleno-substituted porphyrins can also be prepared similarly.
Assuntos
Paládio/química , Porfirinas/síntese química , Sulfetos/química , Catálise , Ligantes , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/químicaRESUMO
[reaction: see text] Iron(III) porphyrin complexes Fe(Por)Cl are effective catalysts for aziridination of alkenes using bromamine-T as the nitrene source. The catalytic system can operate under mild conditions with alkenes as limiting reagents. The aziridination reaction is general and suitable for a wide variety of alkenes, including aromatic, aliphatic, cyclic, and acyclic olefins, as well as alpha,beta-unsaturated esters. For 1,2-disubstituted olefins, the reactions proceeded with moderate to low stereospecificity.
Assuntos
Alcenos/química , Aziridinas/síntese química , Compostos de Ferro/química , Compostos Organometálicos/química , Porfirinas/química , Sulfonamidas/química , Alcenos/síntese química , Catálise , Estrutura MolecularRESUMO
A series of meso-amidoporphyrins were facilely synthesized by direct reactions of meso-brominated porphyrins with amides via palladium-catalyzed amidation reaction. Using a combination of palladium precursor Pd(OAc)(2) or Pd(2)(dba)(3) and phosphine ligand Xantphos, both 5-bromo-10,20-diphenylporphyrin and 5,15-dibromo-10,20-diphenylporphyrin, as well as their zinc complexes, can be effectively coupled with a wide variety of amides to give the corresponding mono- and bis-substituted meso-amidoporphyrins in high yields under mild conditions. [reaction: see text]
Assuntos
Amidas/química , Paládio/química , Porfirinas/química , Porfirinas/síntese química , Bromo/química , Catálise , Ligantes , Estrutura MolecularRESUMO
Cobalt(II) porphyrin complexes were shown to be general and efficient catalysts for selective cyclopropanation of alkenes with ethyl diazoacetate (EDA). The catalytic system can operate with alkenes as limiting reagents, requiring only stoichiometric amounts of EDA. The protocol is performed in one-pot fashion without the need of slow addition of EDA. The diastereoselectivity of the current system can be tuned by using different porphyrin ligands or additives, giving either trans- or cis-dominant cyclopropanes. The asymmetric cyclopropanation was also demonstrated with the use of chiral cobalt porphyrin complexes.
RESUMO
Daidzin, the active principle of an herbal remedy for 'alcohol addiction', has been shown to reduce alcohol consumption in all laboratory animals tested to date. Correlation studies using structural analogues of daidzin suggests that it acts by raising the monoamine oxidase (MAO)/mitochondrial aldehyde dehydrogenase (ALDH-2) activity ratio (J. Med. Chem. 2000, 43, 4169). Structure-activity relationship (SAR) studies on the 7-O-substituted analogues of daidzin have revealed structural features important for ALDH-2 and MAO inhibition (J. Med. Chem. 2001, 44, 3320). We here evaluated effects of substitutions at 2, 5, 6, 8, 3' and 4' positions of daidzin on its potencies for ALDH-2 and MAO inhibition. Results show that analogues with 4'-substituents that are small, polar and with hydrogen bonding capacities are most potent ALDH-2 inhibitors, whereas those that are non-polar and with electron withdrawing capacities are potent MAO inhibitors. Analogues with a 5-OH group are less potent ALDH-2 inhibitors but are more potent MAO inhibitors. All the 2-, 6-, 8- and 3'-substituted analogues tested so far do not inhibit ALDH-2 and/or have decreased potencies for MAO inhibition. This, together with the results obtained from previous studies, suggests that a potent antidipsotropic analogue would be a 4',7-disubstituted isoflavone. The 4'-substituent should be small, polar, and with hydrogen bonding capacities such as, -OH and -NH(2); whereas the 7-substituent should be a straight-chain alkyl with a terminal polar function such as -(CH(2))(n)-OH with 2< or =n < or =6, -(CH(2))(n)-COOH with 5< or =n < or =10, or -(CH(2))(n)-NH(2) with n > or =4.
Assuntos
Dissuasores de Álcool/síntese química , Alcoolismo/prevenção & controle , Isoflavonas/síntese química , Dissuasores de Álcool/farmacologia , Aldeído Desidrogenase/antagonistas & inibidores , Aldeído-Desidrogenase Mitocondrial , Animais , Cricetinae , Técnicas In Vitro , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/enzimologia , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Relação Estrutura-AtividadeRESUMO
[reaction: see text] meso-Aryloxy- and alkoxy-substituted porphyrins were conveniently synthesized by direct reactions of meso-halogenated porphyrins with alcohols via palladium-catalyzed C-O cross-coupling reactions. Using a combination of palladium precursor Pd(OAc)(2) or Pd(2)(dba)(3) and phosphine ligand DPEphos or Xantphos allowed both 5-bromo-10,20-diarylporphyrin and 5,15-dibromo-10,20-diarylporphyrin, as well as their zinc complexes, to be effectively coupled with a variety of alcohols to give the corresponding mono- and bis-substituted meso-aryloxy/alkoxyporphyrins in moderate to high yields under mild conditions.
RESUMO
A new alkaloid, 7-hydroxy-4-(5'-hydroxymethylfuran-2'-yl)-2-quinolone (1), and a new nitrile derivative, 3alpha,4beta-dihydroxy-6-oxo-1-cyclohexene-1-acetonitrile (2), together with three known oxoaporphine alkaloids, were isolated from the whole plant of Aquilegia ecalcarata. Their structures were established on the basis of spectral evidence. Their in vitro cytotoxicity against different classes of cancer cell lines, including GLC-82 and HCT were determined. The new alkaloid 1 [IC 50 (GLC-82) 8.8 +/- 0.2 microM, IC 50 (HCT) 10.1 +/- 0.3 microM] and hernandonine ( 3) [IC 50 (GLC-82) 7.6 +/- 0.5 microM, IC 50 (HCT) 8.2 +/- 0.5 microM] exhibited cytotoxicity towards the cancer cell lines.