RESUMO
We report that hirsutinolide series, 6, 7, 10, 11, 20, and 22, and the semisynthetic analogues, 30, 31, 33, and 36, inhibit constitutively active signal transducer and activator of transcription (Stat)3 and malignant glioma phenotype. A position 13 lipophilic ester group is required for activity. Molecular modeling and nuclear magnetic resonance structural analyses reveal direct hirsutinolide:Stat3 binding. One-hour treatment of cells with 6 and 22 also upregulated importin subunit α-2 levels and repressed translational activator GCN1, microtubule-associated protein (MAP)1B, thioredoxin reductase (TrxR)1 cytoplasmic isoform 3, glucose-6-phosphate 1-dehydrogenase isoform a, Hsp105, vimentin, and tumor necrosis factor α-induced protein (TNAP)2 expression. Active hirsutinolides inhibited anchorage-dependent and three-dimensional spheroid growth, survival, and migration of human glioma lines and glioma patients' tumor-derived xenograft cells harboring constitutively active Stat3. Oral gavage delivery of 6 or 22 inhibited human glioma tumor growth in subcutaneous mouse xenografts. The inhibition of Stat3 signaling represents part of the hirsutinolide-mediated mechanisms to induce antitumor effects.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Glioma/metabolismo , Glioma/patologia , Glucosefosfato Desidrogenase/metabolismo , Proteínas de Choque Térmico HSP110/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-Atividade , Tiorredoxina Redutase 1/metabolismo , Transativadores/metabolismo , Vimentina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , alfa Carioferinas/metabolismoRESUMO
We investigated the use of infrared vibrational frequency of ligands as a potential novel molecular descriptor in three different molecular target and chemical series. The vibrational energy of a ligand was approximated from the sum of infrared (IR) absorptions of each functional group within a molecule and normalized by its molecular weight (MDIR). Calculations were performed on a set of 4-aminoquinazolines with similar docking scores for the VEGFR2/KDR receptor. 4-Aminoquinazolines with MDIR values ranging 192-196 provided compounds with KDR inhibitory activity. The correlation of KDR inhibitory activity was similarly observed in a separate chemical series, the pyrazolo[1,5-a]pyrimidines. Initial exploration of this molecular descriptor supports a tool for rapid lead optimization in the 4-aminoquinazoline chemical series and a potential method for scaffold hopping in pursuit of new inhibitors.
Assuntos
Aminas/síntese química , Inibidores de Proteínas Quinases/síntese química , Quinazolinas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Aminas/química , Desenho de Fármacos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Quinazolinas/químicaRESUMO
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice.
Assuntos
Ftalazinas/farmacocinética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Feminino , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Camundongos , Camundongos Endogâmicos , Ftalazinas/administração & dosagem , Ftalazinas/síntese química , Piperidinas , Quinazolinas , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
A novel class of 1-(isoquinolin-5-yl)-4-arylamino-phthalazines is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity with an IC(50) as low as 0.017 microM in an HTRF enzymatic assay. The compounds also inhibit VEGFR-1, a related tyrosine kinase.
Assuntos
Isoquinolinas/farmacologia , Ftalazinas/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fluorimunoensaio , Humanos , Concentração Inibidora 50 , Isoquinolinas/síntese química , Ftalazinas/síntese química , Relação Estrutura-AtividadeRESUMO
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.
Assuntos
Antimitóticos/síntese química , Antimitóticos/farmacologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Animais , Antimitóticos/química , Antimitóticos/classificação , Biopolímeros/química , Biopolímeros/metabolismo , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/classificação , Conformação Proteica/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A novel class of 4-arylamino-phthalazin-1-yl-benzamides is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display potent VEGFR-2 inhibitory activity with an IC50 as low as 0.078 microM in an HTRF enzymatic assay. These compounds are relatively selective against a small kinase panel.
Assuntos
Inibidores da Angiogênese/síntese química , Ftalazinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Concentração Inibidora 50 , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Cross-conjugated alkylidene prostaglandins have been shown to be potent cytostatic agents that exert their action through a unique and unusual mechanism. Compounds in this class also inhibit viral replication and have a role in osteogenesis and adipogenesis; consequently, they are of considerable current interest as pharmaceutical lead compounds. The purpose of our research was to define an efficent protocol for the assembly of the C-10 trifluoromethyl prostanoid mentioned in the title. This compound was predicted to show strong antitumor activity on the basis of the known structure-activity relationships within this series. A novel strategy for assembling the carbon skeleton of Delta(7)-unsaturated prostanoids bearing oxygen functionality at C-12 through an ionic electrocyclic process has been described. Key steps of the synthesis are the preparation of dieneone 14b through an electrocyclic ring-opening reaction and the ionic electrocyclization of 26a, which creates the functionalized carbon skeleton. The target compound was found to be cytotoxic in vitro against two human tumor cell lines in the low &mgr;M range, confirming our prediction.