RESUMO
We describe the synthesis of 26 compounds, small polycerasoidol analogs, that are Lipinski's rule-of-five compliant. In order to confirm key structural features to activate PPARα and/or PPARγ, we have adopted structural modifications in the following parts: (i) the benzopyran core (hydrophobic nucleus) by benzopyran-4-one, dihydrobenzopyran or benzopyran-4-ol; (ii) the side chain at 2-position by shortening to C3, C4 and C5-carbons versus C-9-carbons of polycerasoidol; (iii) the carboxylic group (polar head) by oxygenated groups (hydroxyl, acetoxy, epoxide, ester, aldehyde) or non-oxygenated motifs (allyl and alkyl). Benzopyran-4-ones 6, 12, 13 and 17 as well as dihydrobenzopyrans 22, 24 and 25 were able to activate hPPARα, whereas benzopyran-4-one (7) with C5-carbons in the side chain exhibited hPPARγ agonism. According to our previous docking studies, SAR confirm that the hydrophobic nucleus (benzopyran-4-one or dihydrobenzopyran) is essential to activate PPARα and/or PPARγ, and the flexible linker (side alkyl chain) should containg at least C5-carbon atoms to activate PPARγ. By contrast, the polar head ("carboxylic group") tolerated several oxygenated groups but also non-oxygenated motifs. Taking into account these key structural features, small polycerasoidol analogs might provide potential active molecules useful in the treatment of dyslipidemia and/or type 2 diabetes.
Assuntos
Benzopiranos/síntese química , Benzopiranos/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Benzopiranos/química , Descoberta de Drogas , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Ten acetogenins, one of them new, were isolated from leaves and twigs of a Bolivian collection of Annona montana. The new compound that we named tucupentol (1) is a mono-tetrahydrofuran-pentahydroxy-acetogenin. The inhibitory potency of tucupentol (1) on the mitochondrial complex I was evaluated, and this activity was compared with that of the known acetogenins, annonacin-A, cis-annonacin-10-one, aromin, and gigantetronenin, also isolated from this plant material. The mentioned acetogenins acted as selective inhibitors of mitochondrial complex I in the 0.8-5.4-nM range.
Assuntos
Acetogeninas/isolamento & purificação , Acetogeninas/farmacologia , Annona/química , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Furanos/isolamento & purificação , Furanos/farmacologia , Animais , Bolívia , Bovinos , Concentração Inibidora 50 , Mitocôndrias Cardíacas/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Caules de Planta/químicaRESUMO
We describe herein the isolation and semisynthesis of four acetogenin derivatives (1-4) as well as their ability to inhibit the mitochondrial respiratory chain and several tumor cell lines. In addition, four nanoseconds (ns) of MD simulation of compound 4, in a fully hydrated POPC bilayer, is reported.
Assuntos
Antineoplásicos Fitogênicos/biossíntese , Álcoois Graxos/metabolismo , Lactonas/metabolismo , Acetogeninas , Annona/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Transporte de Elétrons/efeitos dos fármacos , Álcoois Graxos/farmacologia , Furanos/farmacologia , Humanos , Ligação de Hidrogênio , Indicadores e Reagentes , Lactonas/farmacologia , Bicamadas Lipídicas , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Fosfatidilcolinas/química , Sementes/químicaRESUMO
Heterocyclic analogues of squamocin have been semisynthesized by condensation reactions between squamocin-derived alpha-keto esters and heterodinucleophiles. The strong complex I inhibitory potency of squamocin-benzimidazole, a hybrid derivative, illustrates for the first time the functional analogy existing between the terminal butenolide of annonaceous acetogenins and heteroaromatic substructures of classic inhibitors of the enzyme. This finding supports the categorization of this atypical group of inhibitors as antagonists of the ubiquinone substrates. In addition, competition experiments of squamocin-benzimidazole versus squamocin and rolliniastatin-2 suggest that the binding of this hybrid inhibitor is responsible for a negative allosteric effect at the level of the first ubiquinone-binding site (A site) of mitochondrial complex I. This result supports the existence of a large cooperatively regulated inhibitor/ubiquinone-binding pocket located within the catalytic core of the enzyme, consisting of the association of the previously defined affinity sites A and B.
Assuntos
Annona/metabolismo , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Álcoois Graxos/metabolismo , Furanos/farmacologia , Lactonas/metabolismo , Acetogeninas , Annona/enzimologia , Complexo I de Transporte de Elétrons/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Ésteres/química , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Furanos/química , Lactonas/química , Lactonas/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/metabolismo , Oxirredução , Rutênio/química , Sementes/metabolismo , Especificidade por SubstratoRESUMO
The antitumoral activity of a series of acetylated bis-tetrahydrofuranic acetogenins with a threo/trans/threo/trans/erythro relative configuration was characterized by four new natural and two semisynthetic, 15,24,30-trioxygenated acetogenins that were found to inhibit mitochondrial complex I enzyme as well as growth of several tumor cell lines. Placement of acetyl groups along the alkyl chain modulated the potency of the bis-tetrahydrofuranic acetogenins and could be important for future utilization of these compounds as chemotherapeutic agents.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Álcoois Graxos/síntese química , Álcoois Graxos/farmacologia , Inibidores do Crescimento/síntese química , Inibidores do Crescimento/farmacologia , Lactonas/síntese química , Lactonas/farmacologia , Acetogeninas , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Álcoois Graxos/química , Inibidores do Crescimento/química , Humanos , Lactonas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Neoplasias/enzimologia , Neoplasias/patologia , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
A new beta-hydroxy-gamma-methyl-gamma-lactone bistetrahydrofuranic acetogenin, tucumanin, with the infrequent symmetrical threo/trans/threo/trans/threo relative configuration at the tetrahydrofuran rings was isolated from Annona cherimolia (Annonaceae) seeds. The inhibitory potency on the mitochondrial complex I of acetogenins with this relative configuration (tucumanin and asimicin)was compared with that shown by the corresponding pairs with an asymmetrical threo/trans/threo/trans/erythro relative configuration (laherradurin/rolliniastatin-2, and itrabin/molvizarin). All these compounds act as selective inhibitors of mitochondrial complex I in the 0.18 - 1.55 nM range.