ABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Brain Neoplasms/drug therapy , Glioma/drug therapy , Animals , Antineoplastic Agents/chemical synthesis , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Line, Tumor , Drug Evaluation, Preclinical/methods , Female , Glioma/metabolism , Glioma/pathology , Glucosephosphate Dehydrogenase/metabolism , HSP110 Heat-Shock Proteins/metabolism , Humans , Magnetic Resonance Spectroscopy , Mice, Nude , Microtubule-Associated Proteins/metabolism , Molecular Docking Simulation , Molecular Structure , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Structure-Activity Relationship , Thioredoxin Reductase 1/metabolism , Trans-Activators/metabolism , Vimentin/metabolism , Xenograft Model Antitumor Assays , alpha Karyopherins/metabolismABSTRACT
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.
Subject(s)
Amines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Amines/chemistry , Drug Design , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Quantitative Structure-Activity Relationship , Quinazolines/chemistryABSTRACT
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.
Subject(s)
Phthalazines/pharmacokinetics , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Female , Isoquinolines/chemical synthesis , Isoquinolines/pharmacokinetics , Mice , Mice, Inbred Strains , Phthalazines/administration & dosage , Phthalazines/chemical synthesis , Piperidines , Quinazolines , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitorsABSTRACT
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.
Subject(s)
Isoquinolines/pharmacology , Phthalazines/pharmacology , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Fluoroimmunoassay , Humans , Inhibitory Concentration 50 , Isoquinolines/chemical synthesis , Phthalazines/chemical synthesis , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Antimitotic Agents/chemical synthesis , Antimitotic Agents/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Tubulin/chemistry , Tubulin/metabolism , Animals , Antimitotic Agents/chemistry , Antimitotic Agents/classification , Biopolymers/chemistry , Biopolymers/metabolism , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/classification , Protein Conformation/drug effects , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Phthalazines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Angiogenesis Inhibitors/pharmacology , Inhibitory Concentration 50 , Phthalazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitorsABSTRACT
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.