6533b874fe1ef96bd12d632a

RESEARCH PRODUCT

Synthesis of novel antimitotic agents based on 2-amino-3-aroyl-5-(hetero)arylethynyl thiophene derivatives

Pier Giovanni BaraldiStefania GrimaudoAntonietta Di CristinaErnest HamelMaria Rosaria PipitoneAndrea BrancaleRomeo RomagnoliJan BalzariniManlio TolomeoOlga Cruz-lopez

subject

KetoneCell divisionStereochemistryClinical BiochemistryPharmaceutical ScienceSonogashira couplingUterine Cervical NeoplasmsEthermacromolecular substancesThiophenesAntimitotic AgentsBiochemistryChemical synthesisArticlechemistry.chemical_compoundMiceStructure-Activity RelationshipThiopheneCell Line TumorDrug DiscoveryThiopheneAnimalsHumansInhibition of tumor cell growthMolecular BiologyCell Proliferationchemistry.chemical_classificationLeukemiaMolecular StructureInhibition of tubulin polymerizationCell growthArylOrganic ChemistryAntiproliferative agentsAntiproliferative agents; Inhibition of tubulin polymerization; Inhibition of tumor cell growth; Thiophene;chemistryMolecular MedicineFemale

description

Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for cancer therapy. In search of new compounds with strong antiproliferative activity and simple molecular structure, a new series of 2-amino-3-(3',4',5'-trimethoxybenzoyl)-5-(hetero)aryl ethynyl thiophene derivatives was prepared by the Sonogashira coupling reaction of the corresponding 5-bromothiophenes with several (hetero)aryl acetylenes. When these compounds were analyzed in vitro for their inhibition of cell proliferation, the 2- and 3-thiophenyl acetylene derivatives were the most powerful compounds, both of which exerted cytostatic effects at submicromolar concentrations. In contrast, the presence of a more flexible ethyl chain between the (hetero)aryl and the 5-position of the thiophene ring resulted in significant reduction in activity relative to the 5-(hetero)aryl acetylene substituted derivatives. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. We found that the antiproliferative effects of the most active compounds were associated with increase of the proportion of cells in the G(2)/M and sub-G(1) phases of the cell cycle. ispartof: Bioorganic & Medicinal Chemistry Letters vol:21 issue:9 pages:2746-51 ispartof: location:England status: published

yearjournalcountryeditionlanguage
2011-05-01
10.1016/j.bmcl.2010.11.083http://hdl.handle.net/11392/1428110