ABSTRACT
New series of 2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-ones and 3,4,5,10-tetrahydro-2H-diazepino[3,4-b]indol-1-ones have been synthesized through an iodolactonisation/lactone-to-lactam rearrangement sequence. These compounds were evaluated as potential protein kinase inhibitors (CDK1, CDK5 and GSK-3). 11-Iodo-2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-one derivatives exhibited sub-micromolar inhibitory activity against cyclin-dependent kinases. Docking studies were realized to determine the binding mode of the inhibitors into the ATP binding domain of the CDK5 catalytic site. Our result highlighted two weak Van-der-Waals bonding interactions established between the iodine atom and both phenyl group of Phe 80 and ammonium end of Lys 33.
Subject(s)
Cyclin-Dependent Kinases/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Animals , Catalytic Domain , Chemistry Techniques, Synthetic , Cyclin-Dependent Kinases/chemistry , Cyclin-Dependent Kinases/metabolism , Humans , Indoles/chemistry , Indoles/metabolism , Molecular Docking Simulation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Structure-Activity RelationshipABSTRACT
Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.
Subject(s)
Aromatase Inhibitors/chemistry , Aromatase Inhibitors/pharmacology , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Steryl-Sulfatase/antagonists & inhibitors , Triazoles/chemistry , Triazoles/pharmacology , Animals , Aromatase Inhibitors/chemical synthesis , Biphenyl Compounds/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Female , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Rats , Rats, Wistar , Spectrometry, Mass, Electrospray Ionization , Steryl-Sulfatase/metabolism , Structure-Activity Relationship , Triazoles/chemical synthesisABSTRACT
The synthesis of new N-homopiperazinyl-based ligands is reported. Various structural modifications along with the corresponding biological activities on 5-HT(1A)/5-HT(7) receptors give further insights into this class of serotoninergic ligands. Among the tested central heterocyles, the 7-azaindole gave the best results on the above-mentioned receptors.
Subject(s)
Piperazines/chemistry , Serotonin Receptor Agonists/chemistry , Drug Design , Humans , Indoles , Ligands , Piperazine , Piperazines/chemical synthesis , Piperazines/pharmacology , Protein Binding , Radioligand Assay , Receptor, Serotonin, 5-HT1A , Receptors, Serotonin , Serotonin Receptor Agonists/chemical synthesis , Structure-Activity RelationshipABSTRACT
Several small weight indole derivatives (D-64131, D-24851, BPR0L075, BLF 61-3, and ATI derivatives) are potent tubulin polymerization inhibitors and show nanomolar antiproliferative activity. Among them, indolobenzazepin-7-ones were recently disclosed as potent antimitotic agents. In an effort to improve this structure, we prepared new derivatives in order to evaluate their antiproliferative activity. 5,6,7,9-Tetrahydro-8H-indolo[2,3-e][3]benzazocin-8-one (1m) was found to be the most potent derivative inhibiting the cell growth of several cancer cell lines in the lower nanomolar range.