ABSTRACT
Compounds with activity at serotonin (5-hydroxytryptamine) 5-HT2 and α1 adrenergic receptors have potential for the treatment of central nervous system disorders, drug addiction or overdose. Isolaureline, dicentrine and glaucine enantiomers were synthesized, and their in vitro functional activities at human 5-HT2 and adrenergic α1 receptor subtypes were evaluated. The enantiomers of isolaureline and dicentrine acted as antagonists at 5-HT2 and α1 receptors with (R)-isolaureline showing the greatest potency (pKb = 8.14 at the 5-HT2C receptor). Both (R)- and (S)-glaucine also antagonized α1 receptors, but they behaved very differently to the other compounds at 5-HT2 receptors: (S)-glaucine acted as a partial agonist at all three 5-HT2 receptor subtypes, whereas (R)-glaucine appeared to act as a positive allosteric modulator at the 5-HT2A receptor.
Subject(s)
Aporphines/chemistry , Receptor, Serotonin, 5-HT2A/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Serotonin/chemistry , Adrenergic alpha-1 Receptor Agonists/chemistry , Adrenergic alpha-1 Receptor Agonists/metabolism , Aporphines/metabolism , Binding Sites , HEK293 Cells , Humans , Kinetics , Molecular Docking Simulation , Protein Structure, Tertiary , Receptor, Serotonin, 5-HT2A/chemistry , Receptor, Serotonin, 5-HT2A/genetics , Receptors, Adrenergic, alpha-1/chemistry , Receptors, Adrenergic, alpha-1/genetics , Serotonin/metabolism , Serotonin 5-HT2 Receptor Agonists/chemistry , Serotonin 5-HT2 Receptor Agonists/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
This study seeks to investigate the relationship between the structural modification and bioactivity of a series of tribenzyltin complexes with different ligands and substitutions. Complexation with the N,N-diisopropylcarbamothioylsulfanylacetate or isonicotinate ligands enhanced the anticancer properties of tribenzyltin compounds via delayed cancer cell-cycle progression, caspase-dependent apoptosis induction, and significant reduction in cell motility, migration and invasion. Halogenation of the benzyl ring improved the anticancer effects of the tribenzyltin compounds with the N,N-diisopropylcarbamothioylsulfanylacetate ligand. These compounds also demonstrated far greater anticancer effects and selectivity than cisplatin and doxorubicin, which provides a rationale for their further development as anticancer agents.
Subject(s)
Antineoplastic Agents/chemistry , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Cell Movement/drug effects , Neoplasm Invasiveness/prevention & control , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Female , Humans , Ligands , Structure-Activity RelationshipABSTRACT
The two Sn-O-C-C-C-O chelate rings in the title compound, [Sn(C(15)H(11)O(2))(2)Cl(2)]·0.5C(7)H(8), adopt envelope conformations, with the Sn atom deviating from the least-squares plane passing through the C and O atoms by 0.626â (1)â Å in one ring and by 0.690â (1)â Å for the other. The two planes are aligned at an angle of 59.6â (1)°. The Cl atoms occupy cis positions in the octa-hedral SnCl(2)O(4) coordination environment. The solvent mol-ecule is disordered about a center of inversion.
