RESUMO
BACKGROUND/AIM: Based on the cytotoxic agent (-)-zampanolide, N,N'-(arylmethylene)bisamides were designed and synthesized as candidate anti-cancer agents. Among them, N,N'-[(3,4-dimethoxyphenyl)methylene]biscinnamide (DPMBC) was identified as the most potent cytotoxic analog against cancer cells. In this study, we investigated the mechanisms underlying DPMBC-induced cell death in HL-60 human promyelocytic leukemia and PC-3 human prostate cancer cells. MATERIALS AND METHODS: Cell growth was assessed by the WST-8 assay. Induction of apoptosis was assessed by nuclear morphology, DNA ladder formation, and flow cytometry using Annexin V staining. Activation of factors in the apoptotic signaling pathway was assessed by western blot analyses. Knockdown of death receptor 5 (DR5) was performed using siRNA. RESULTS: DPMBC up-regulated expression levels of DR5 protein and induced apoptosis through the extrinsic apoptotic pathway mediated by DR5 and caspases. CONCLUSION: DPMBC is an extrinsic apoptosis inducer, which has potential as a therapeutic agent for cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Macrolídeos/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Antineoplásicos/química , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fragmentação do DNA , Relação Dose-Resposta a Droga , Humanos , Macrolídeos/química , Estrutura Molecular , RNA Interferente Pequeno/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismoRESUMO
(+)-5-Thiosucrose 1, a novel isosteric sulfur analog of sucrose, was synthesized stereoselectively for the first time via indirect ß-d-fructofuranosidation involving selective ß-d-psicofuranosidation, followed by stereo-inversion of the secondary hydroxy group at the C-3 position on the furanose ring. Glycosidation of protected 5-thio-d-glucose with a d-psicofuranosyl donor provided ß-d-psicofuranosyl 5-thio-α-d-glucopyranoside and that with d-fructofuranosyl donor gave α-d-fructofuranosyl 5-thio-α-d-glucopyranoside. Two anomeric stereocenters of the glycosyl donor and acceptor were controlled correctly to provide a single disaccharide among four possible anomeric isomers in the glycosylation. Conversion of the resulting disaccharides afforded (+)-5-thiosucrose 1 and (+)-5-thioisosucrose 2 in excellent yields, respectively. Inhibitory activities of 1 and 2 against α-glucosidase in vitro were also examined.
RESUMO
Here we report the construction of highly functionalized chiral 1,1,2,3-tetrasubstituted arylcyclopropanes of medicinal chemical importance using Pd(II)-catalyzed arylation via directing group-mediated C(sp3)-H activation. The key aspect for the effective arylation was control of the substrate conformation based on the characteristic steric and stereoelectronic features of cyclopropane by manipulating the protecting group at the hydroxyl. The arylation with good functional group tolerance is pivotal as the first entry to chiral 1,1,2,3-tetrasubstituted arylcyclopropanes with wide variety of aryl groups, including heteroaryl groups.
RESUMO
Goniodenin is a lipophilic polyketide originating from plant sources and which possesses a potent cytotoxic activity against cancer cell lines. The first total synthesis of (+)-goniodenin has been achieved in 23 steps from (R)-glycidol. The synthetic sequence featured a cross metathesis for the formation of the C8-C9 bond and installation of the terminal γ-butenolactone ring unit by the alkylation of α-phenylthio-γ-butyrolactone with the corresponding C3-O-triflate. The stereogenic center at C18 carbon was created by Hiyama-Fujita reduction of the corresponding ketone with high diastereoselectivity.
Assuntos
Acetogeninas/síntese química , Policetídeos/síntese química , 4-Butirolactona/química , Alquilação , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ciclização , Policetídeos/química , Policetídeos/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas de Bombardeamento Rápido de Átomos , EstereoisomerismoRESUMO
Pd(II)-catalyzed ring formation of 2,3,5-trisubstituted and 2,3,4,5-tetrasubstituted tetrahydrofurans is described. Oxypalladation of a chiral ε-hydroxy allylic alcohol provides a 5-alkenyltetrahydrofuran ring in excellent yields via a 5-exo-trigonal process. Nine substrates including six secondary allylic alcohols and three primary allylic alcohols with or without an additional secondary hydroxy substituent at the γ-position have been examined. Their structures are restricted by a 2,2,4,4-tetraisopropyl-1,3,5,2,4-trioxadisilocane ring. The stereochemistry of the resulting tetrahydrofuran products was determined by chemical transformation. The reaction mechanism is discussed on the basis of the stereochemical results. The steps in the chiral allylic alcohol directed or the nucleophilic alcohol directed facial selection for the formation of the alkene-Pd(II)-π-complex, the cis-oxypalladation, and a syn-elimination mechanism account for the observed stereochemistry of the reaction.
RESUMO
γ-Glutamylcyclotransferase (GGCT) is an important enzyme that cleaves γ-glutamyl-amino acid in the γ-glutamyl cycle to release 5-oxoproline and amino acid. Eighteen N-acyl-L-alanine analogues including eleven new compounds have been synthesized and examined for their inhibitory activity against recombinant human GGCT protein. Simple N-glutaryl-L-alanine was found to be the most potent inhibitor for GGCT. Other N-glutaryl-L-alanine analogues having methyl and dimethyl substituents at the 2-position were moderately effective, while N-(3R-aminoglutary)-L-alanine, the substrate having an (R)-amino group at the 3-position or N-(N-methyl-3-azaglutaryl)-L-alanine, the substrate having an N-methyl substituent on the 3-azaglutaryl carbon, in constract, exhibited excellent inhibition properties.
Assuntos
Alanina/análogos & derivados , Alanina/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , gama-Glutamilciclotransferase/antagonistas & inibidores , Alanina/química , Alanina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , gama-Glutamilciclotransferase/metabolismoRESUMO
Cytotoxic acetogenin (+)-goniocin has been synthesized in 17 steps from (R)-O-tritylglycidol. The core structure of the contiguous C22-C10 threo-trans-threo-trans-threo-trans-tris-tetrahydrofuran (THF) ring involving an iterative THF-ring unit was synthesized. An iterative THF ring unit was constructed from an alkenyl-substituted THF ring in four steps including a Pd(II)-catalyzed ring-closing reaction and cross-metathesis. This method is general and allows the preparation of both trans-threo-trans- and trans-threo-cis-THF ring units flexibly.
RESUMO
A Pd(OAc)2-catalyzed alkylation reaction of the tertiary carbon of chiral cyclopropane substrates with alkyl iodides and bromides via C(sp(3))-H activation has been developed. This is an elusive example of a C-H activation-mediated alkylation of tertiary carbon to effectively construct a quaternary carbon center. The alkylation proceeded with various alkyl halides, including those of functional groups, to provide a variety of chiral cis- and trans-1,1,2,-trialkyl substituted cyclopropanes of medicinal chemical importance.
Assuntos
Ciclopropanos/síntese química , Paládio/química , Alquilação , Catálise , Ciclopropanos/química , Estrutura Molecular , EstereoisomerismoRESUMO
A formal synthesis of (-)-schulzeine B, a marine natural alkaloid possessing potent antidiabetic activity, has been achieved. A benzo[a]quinolizidin-4-one is a common skeleton of schulzeines (A-C). (-)-Schulzeine B possesses an (S)-stereogenic center at the C-3 carbon. The chiral (3S,11bS)-3-amino-9,11-dimethoxybenzo[a]quinolizidin-4-one has been prepared efficiently from (2-bromo-3,5-dihydroxyphenyl)acetonitrile in 17 steps including (i) a dehydrative intramolecular amination catalyzed by HClO4 and (ii) a proline or boric acid catalyzed transcycloamidation reaction for the construction of the δ-lactam ring.
Assuntos
Acetonitrilas/química , Alcaloides/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Lactamas/síntese química , Quinolizidinas/química , Alcaloides/química , Aminação , Catálise , Ciclização , Compostos Heterocíclicos com 3 Anéis/química , Lactamas/química , Estrutura Molecular , EstereoisomerismoRESUMO
The asymmetric desymmetrization of meso-2-alkynylbenzenediols through the use of a combination of axially chiral diphosphine(AuCl)2 precatalysts and silver salt co-catalysts gave optically active isochromene compounds with high enantioselectivities in good yields. The corresponding DL-diol isomers underwent efficient kinetic resolution to give the cyclized isochromenes and recovered diols with high enantioselectivities under similar conditions. The high reactivity and selectivity in the desymmetrization of the meso-diols is independent of the combination of axially chiral diphosphine(AuCl)2 precatalyst and silver salt co-catalyst, whereas the corresponding tricarbonylchromium complexes of alkynylbenzenediols were affected by the combination of the diphosphine(AuCl)2 and silver salt. The reactivity was largely dependent on the nature of the gold(I) species.
Assuntos
Ouro/química , Prata/química , Catálise , Ciclização , Filtração , Isomerismo , Cinética , Estrutura Molecular , EstereoisomerismoRESUMO
Gold(I)-catalyzed asymmetric intramolecular cyclization of prochiral 1,3-dihydroxymethyl-2-alkynylbenzene or 1,3-bis(carbamate)-2-alkynylbenzene tricarbonylchromium complexes with axially chiral diphosphine ligand gave planar chiral tricarbonylchromium complexes of 1H-isochromene or 1,2-dihydroisoquinoline with high enantioselectivity. An enantiomeric excess of the planar chiral arene chromium complexes was largely affected by a combination of axially chiral diphosphine(AuCl)2 precatalysts and silver salts. In the case of 1,3-dihydroxymethyl-2-alkynylbenzene chromium complexes, a system of segphos(AuCl)2 with AgBF4 resulted in the formation of the corresponding antipode.
Assuntos
Alcinos/química , Benzopiranos/síntese química , Cromo/química , Ouro/química , Compostos Organometálicos/síntese química , Benzopiranos/química , Catálise , Compostos Organometálicos/química , EstereoisomerismoRESUMO
Asymmetric total syntheses of the 1-phenethyl-1,2,3,4-tetrahydroisoquinoline alkaloids (+)-dysoxyline (1), (+)-colchiethanamine (2), and (+)-colchiethine (3) are described. In the synthetic routes, coupling of a key, enatiomerically pure 1-(sulfonylmethyl)tetrahydroisoquinoline with aromatic aldehydes, performed by using the Julia-Kocienski reaction, afforded the corresponding 1-(ß-styryl)-substituted tetrahydroisoquinolines with complete retention of the absolute configuration at the C1 carbon atom. Functionalization of the products generated in these processes by using four- or five-step sequences gave the target alkaloids 1-3.
Assuntos
Alcaloides/química , Alcaloides/síntese química , Isoquinolinas/química , Isoquinolinas/síntese química , Alcenos/química , Técnicas de Química SintéticaRESUMO
The total synthesis of (-)-apicularen A (1), a highly cytostatic 12-membered macrolide, and its analogues is described. The convergent and distinct approach not only provides 1, but also opens the opportunity to synthesize C10-C11 functional analogues of 1. The key steps of the total synthesis include assembling of iodoalkene 12 and aldehyde 13by Nozaki-Hiyama-Kishi (NHK) coupling, stereospecific construction of 2,6-trans-disubstituted dihydropyran by Pd(II)-catalyzed 1,3-chirality transfer reaction, and Yamaguchi macrolactonization. The (17E,20Z,22Z)-heptadienoylenamine moiety in the side chain is installed by an efficient Cu(I)-mediated coupling to complete the synthesis. Analogues of C11-epi-, C11-deoxy-C10-α-hydroxy-, and C10-C11 dehydrated apicularen A 3-5 were also prepared. Cytostatic activities of (-)-apicularen A and the three analogues for three different cancer cell lines are described.
Assuntos
Antineoplásicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Antineoplásicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Catálise , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Paládio/química , EstereoisomerismoRESUMO
N-[2-(2,4-Difluorophenoxy)trifluoromethyl-3-pyridyl]sulfonamide derivatives 3-6 were prepared by the reaction of 3-pyridylamines and sulfonyl chlorides. Inhibitory activities of these compounds toward secretory phospholipase A2 (sPLA2) were examined and N-[2-(2,4-difluorophenoxy)-5-trifluoromethyl-3-pyridyl]-2-naphthalenesulfonamide (5c) was found to be the most potent against sPLA2 with an IC50 value of 90 µM.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fosfolipases A2 Secretórias/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Inibidores Enzimáticos/metabolismo , Concentração Inibidora 50 , Fosfolipases A2 Secretórias/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
A series of N-(trifluoromethyl-2-pyridinyl)alkane- and arenesulfonamides 2-5 have been synthesized by the substitution reaction of 2-chloro(trifluoromethyl)pyridines 6 with alkane- and arenesulfonamides 7. Their inhibitory activities against secretory phospholipase A2 of porcine pancreas were examined and the analog N-[4,5-bis(trifluoromethyl)-2-pyridinyl]-4-trifluoromethylbenzenesulfonamide 4i was shown to have the highest inhibitory activity, with an IC(50) value of 0.58 mM.
Assuntos
Inibidores Enzimáticos/química , Fosfolipases A2 Secretórias/antagonistas & inibidores , Piridinas/química , Sulfonamidas/química , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pâncreas/enzimologia , Fosfolipases A2 Secretórias/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , SuínosRESUMO
The crystal structures of α-D-glucopyranosyl ß-D-psicofuranoside and α-D-galactopyranosyl ß-D-psicofuranoside were determined by a single-crystal X-ray diffraction analysis, refined to R(1)=0.0307 and 0.0438, respectively. Both disaccharides have a similar molecular structure, in which psicofuranose rings adopt an intermediate form between (4)E and (4)T(3). Unique molecular packing of the disaccharides was found in crystals, with the molecules forming a layered structure stacked along the y-axis.
Assuntos
Dissacarídeos/química , Configuração de Carboidratos , Cristalografia por Raios X , Modelos MolecularesRESUMO
A Pd(II)-catalyzed cascade reaction of chiral nonracemic allylic alcohols possessing an internal mono- or diepoxide and a terminal alcohol provided a contiguous THF-THF ring unit stereospecifically. The cyclization takes place in a 5-exo-tet-5-exo-trig fashion with high chirality transfer through a syn-S(N)2' like process for the formation of the internal THF ring. Chiral bis- and tris-THF-THF ring units were effectively prepared from acyclic precursors by the Pd-catalyzed reaction.
Assuntos
Furanos/síntese química , Paládio/química , Catálise , Ciclização , Compostos de Epóxi/química , Estrutura Molecular , EstereoisomerismoRESUMO
The intramolecular 1,3-chirality transfer reaction of chiral amino alcohols 1 with 99% ee was developed to construct chiral 1-substituted tetrahydroisoquinoline 2. Bi(OTf)(3) (10 mol %)-catalyzed cyclization of 1 (R = H) afforded (S)-1-(E)-propenyl tetrahydroisoquinoline 2 (R = H) in 83% yield with a ratio of 98:2. The stereochemistry at the newly formed chiral center was produced by a syn S(N)2'-type process. In this reaction, the substituent on the benzene ring of 1 significantly affected the reactivities and selectivities. A plausible reaction mechanism was proposed.
Assuntos
Mesilatos/química , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/síntese química , Catálise , Ciclização , Estrutura Molecular , Paládio , EstereoisomerismoRESUMO
Gold(I)-catalyzed asymmetric cyclization of 1,3-dihydroxymethyl-2-alkynylbenzene chromium complexes gave planar chiral isochromene chromium complexes with high enantioselectivity. Enantiomeric excess of the cyclization products was largely affected by a combination of axially chiral diphosphine(AuCl)(2) precatalysts and silver salts. A system of segphos(AuCl)(2) with AgBF(4) resulted in the formation of the corresponding antipode.
Assuntos
Compostos de Cromo/química , Ouro/química , Catálise , Ciclização , Estrutura Molecular , EstereoisomerismoRESUMO
A convergent total synthesis of (-)-apicularen A, a highly cytostatic 12-membered macrolide, has been accomplished. The key steps include assembling of iodoalkene 8 and aldehyde 9 by Nozaki-Hiyama-Kishi (NHK) coupling, stereospecific construction of 2,6-trans-disubstituted dihydropyran by Pd(II)-catalyzed 1,3-chirality transfer reaction, and Yamaguchi macrolactonization. Introduction of the (2Z,4Z)-heptadienamide moiety in the side chain by an efficient Cu(I)-mediated coupling completed the total synthesis.