6533b851fe1ef96bd12aa1d4
RESEARCH PRODUCT
Pyrrolo[2',3':3,4]cyclohepta[1,2-d][1,2]oxazoles, a New Class of Antimitotic Agents Active against Multiple Malignant Cell Types
Virginia SpanòMarilia BarrecaMarilia BarrecaAnna CarboneGiampietro ViolaPaola BarrajaRuoli BaiStefano AlcaroErnest HamelFrancesco BertoniDaniele GiallombardoRoberta RoccaMaria Valeria RaimondiPierfrancesco TassoneAlessandra MontalbanoEugenio GaudioRoberta Bortolozzisubject
CellsMitosisAntineoplastic AgentsApoptosisAntimitotic AgentsDrug Screening Assays[12]oxazoles antimitotic agents lymphoma tubulin polymerization inhibitorsDose-Response RelationshipStructure-Activity Relationshipchemistry.chemical_compoundModelsDrug DiscoverymedicineHumansStructure–activity relationshipColchicineOxazolesAntimitotic Agents; Antineoplastic Agents; Apoptosis; Cell Proliferation; Cells Cultured; Dose-Response Relationship Drug; Drug Screening Assays Antitumor; G2 Phase Cell Cycle Checkpoints; HeLa Cells; Humans; Mitosis; Models Molecular; Molecular Structure; Oxazoles; Structure-Activity RelationshipCell Proliferationchemistry.chemical_classificationReactive oxygen speciesCulturedMolecular StructureChemistryMolecularDepolarizationAntitumorMolecular biologyG2 Phase Cell Cycle CheckpointsMechanism of actionApoptosisCell cultureMolecular MedicineAntimitotic AgentDrugmedicine.symptomHeLa Cellsdescription
A new class of pyrrolo[2',3':3,4]cyclohepta[1,2-d][1,2]oxazoles was synthesized for the treatment of hyperproliferative pathologies, including neoplasms. The new compounds were screened in the 60 human cancer cell lines of the NCI drug screen and showed potent activity with GI50 values reaching the nanomolar level, with mean graph midpoints of 0.08-0.41 μM. All compounds were further tested on six lymphoma cell lines, and eight showed potent growth inhibitory effects with IC50 values lower than 500 nM. Mechanism of action studies showed the ability of the new [1,2]oxazoles to arrest cells in the G2/M phase in a concentration dependent manner and to induce apoptosis through the mitochondrial pathway. The most active compounds inhibited tubulin polymerization, with IC50 values of 1.9-8.2 μM, and appeared to bind to the colchicine site. The G2/M arrest was accompanied by apoptosis, mitochondrial depolarization, generation of reactive oxygen species, and PARP cleavage.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-09-28 |