title: Synthesis, biological evaluation, and docking studies of gigantol analogs as calmodulin inhibitors.
abstract: Several analogs of gigantol (1) were synthesized to evaluate their effect on the complexes Ca(2+)-calmodulin (CaM) and Ca(2+)-CaM-CaM sensitive phosphodiesterase 1 (PDE1). The compounds belong to four structural groups including, 1,2-diphenylethanes (2-11), diphenylmethanes (13-15), 1,3-diphenylpropenones (16-18), and 1,3-diphenylpropanes (20-22). In vitro enzymatic studies showed that all compounds except 11 inhibited the complex Ca(2+)-CaM-PDE1 with IC(50) values ranging from 9 to 146 μM. On the other hand, all analogs but 11, 12 and 15 quenched the extrinsic fluorescence of the CaM biosensor hCaM-M124C-mBBr to different extent, then revealing different affinities to CaM; their affinity constants (K(m)) values were in the range of 3-80 μM. Molecular modeling studies indicated that all these compounds bound to CaM at the same site that the classical inhibitors trifluoperazine (TFP) and chlorpromazine (CPZ). Some of these analogs could be worthy candidates for developing new anti-tumor, local anesthetics, antidepressants, antipsychotic, or smooth muscle relaxant drugs, with anti-CaM properties due to their good affinity to CaM and the straightforwardness of their synthesis. In addition they could be valuable tools for the study of Ca(2+)-CaM functions.
authors.affiliation: Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, México DF 04510, Mexico. adelfo@prodigy.net.mx
authors.forename: Adelfo
authors.initials: A
authors.lastname: Reyes-Ramírez
authors.forename: Martha
authors.initials: M
authors.lastname: Leyte-Lugo
authors.forename: Mario
authors.initials: M
authors.lastname: Figueroa
authors.forename: Trinidad
authors.initials: T
authors.lastname: Serrano-Alba
authors.forename: Martín
authors.initials: M
authors.lastname: González-Andrade
authors.forename: Rachel
authors.initials: R
authors.lastname: Mata
mesh_terms: D000779:Anesthetics, Local / Q000138:chemical synthesis / Q000737:chemistry; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry; D015374:Biosensing Techniques; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002746:Chlorpromazine / Q000737:chemistry; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D062105:Molecular Docking Simulation; D010276:Parasympatholytics / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D014268:Trifluoperazine / Q000737:chemistry
chemical_list: D000779:Anesthetics, Local; D000928:Antidepressive Agents; D000970:Antineoplastic Agents; D014150:Antipsychotic Agents; D001632:Bibenzyls; D001713:Biphenyl Compounds; D002147:Calmodulin; D010276:Parasympatholytics; D014268:Trifluoperazine; C478099:gigantol; D006139:Guaiacol; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D002746:Chlorpromazine