RESUMO
The cytosolic Hsp90-selective inhibitor TAS-116 has an acceptable safety profile and promising antitumor activity in clinical trials. We examined the binding characteristics of TAS-116 and its analogs to determine the impact of the ligand binding mode on selectivity for cytosolic Hsp90. Analyses of the co-crystal structure of Hsp90 and inhibitor TAS-116 suggest that TAS-116 interacts with the ATP-binding pocket, the ATP lid region, and the hydrophobic pocket. A competitive isothermal titration calorimetry analysis confirmed that a small fragment of TAS-116 (THS-510) docks into the lid region and hydrophobic pockets without binding to the ATP-binding pocket. THS-510 exhibited enthalpy-driven binding to Hsp90α and selectively inhibited cytosolic Hsp90 activity. The heat capacity change of THS-510 binding was positive, likely due to the induced conformational rearrangement of Hsp90. Thus, we concluded that interactions with the hydrophobic pocket of Hsp90 determine potency and selectivity of TAS-116 and derivatives for the cytosolic Hsp90 isoform.
Assuntos
Antineoplásicos/metabolismo , Benzamidas/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Pirazóis/metabolismo , Sítios de Ligação , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Ligação Proteica , TermodinâmicaRESUMO
The molecular chaperone heat shock protein 90 (HSP90) is a promising target for cancer therapy, as it assists in the stabilization of cancer-related proteins, promoting cancer cell growth, and survival. A novel series of HSP90 inhibitors were discovered by structure-activity relationship (SAR)-based optimization of an initial hit compound 11a having a 4-(4-(quinolin-3-yl)-1 H-indol-1-yl)benzamide structure. The pyrazolo[3,4- b]pyridine derivative, 16e (TAS-116), is a selective inhibitor of HSP90α and HSP90ß among the HSP90 family proteins and exhibits oral availability in mice. The X-ray cocrystal structure of the 16e analogue 16d demonstrated a unique binding mode at the N-terminal ATP binding site. Oral administration of 16e demonstrated potent antitumor effects in an NCI-H1975 xenograft mouse model without significant body weight loss.
Assuntos
Benzamidas/química , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Pirazóis/química , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Benzamidas/metabolismo , Benzamidas/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Camundongos Nus , Conformação Molecular , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pirazóis/metabolismo , Pirazóis/uso terapêutico , Quinolinas/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Solubilidade , Relação Estrutura-AtividadeRESUMO
[Structure: see text] The total synthesis of pseudo 2-epibotcinolide (1b) through several featured synthetic approaches has been attained. First, the chiral linear precursors of the nine-membered ring compound is stereoselectively constructed by the asymmetric aldol reaction for producing beta-hydroxy ester units. Second, the key cyclization reaction to form the nine-membered lactone moiety is efficiently achieved by the extremely facile and powerful mixed-anhydride method promoted by 2-methyl-6-nitrobenzoic anhydride (MNBA) with basic promoters.
Assuntos
Decanoatos/síntese química , Lactonas/síntese química , Pironas/síntese química , Botrytis/metabolismo , Ciclização , Decanoatos/metabolismo , Lactonas/metabolismo , Estrutura Molecular , Pironas/metabolismoRESUMO
Octalactin A, an antitumor agent containing an eight-membered lactone moiety, has been stereoselectively prepared by means of enantioselective aldol reactions of selected silyl enolates with achiral aldehydes, promoted by a chiral Sn(II) complex. The medium-sized lactone part was effectively constructed by way of a new and rapid mixed-anhydride lactonization using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a catalytic amount of 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)pyridine 1-oxide (DMAPO). The use of only 5 mol % of DMAP or 2 mol % of DMAPO rapidly promoted formation of the medium-sized ring of the octalactin, demonstrating the remarkable efficiency of the new lactonization protocol.
Assuntos
Antineoplásicos/síntese química , Lactonas/síntese química , Antineoplásicos/química , Lactonas/química , Conformação Molecular , EstereoisomerismoRESUMO
Various carboxylic esters are obtained at room temperature in excellent yields with high chemoselectivities from nearly equimolar amounts of carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic anhydride with triethylamine by the promotion of a basic catalyst such as 4-(dimethylamino)pyridine. A variety of lactones are also prepared in high yields at room temperature from the corresponding omega-hydroxycarboxylic acids with use of 2-methyl-6-nitrobenzoic anhydride in the presence of 4-(dimethylamino)pyridine. A similar reaction occurs with triethylamine when using a catalytic amount of 4-(dimethylamino)pyridine 1-oxide as an effective promoter for the intramolecular condensation reaction. These methods are successfully applied to the synthesis of erythro-aleuritic acid lactone and an eight-membered-ring lactone moiety of octalactins A and B. The efficiency of the cyclizations is compared to those of other reported lactonizations.