6533b872fe1ef96bd12d307a

RESEARCH PRODUCT

Synthesis of 5H-pyrido[3,2-b]pyrrolizin-5-one tripentone analogs with antitumor activity

Anna CarboneSalviana UlloVirginia SpanòPatrizia DianaAlessandra MontalbanoAlessandro AttanzioStella CascioferroPaola BarrajaLuisa TesoriereBarbara ParrinoGirolamo Cirrincione

subject

TripentonesPyridinesAntineoplastic AgentsApoptosisAntiproliferative activity5H-pyrido[3; 2-b]pyrrolizin-5-ones; Antiproliferative activity; Antitumor; Apoptosis; Tripentones; Pharmacology; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry010402 general chemistry01 natural sciencesStructure-Activity Relationship2-b]pyrrolizin-5-onesCell Line TumorNeoplasmsDrug DiscoverymedicineHumansCytotoxic T cellPyrrolesCytotoxicityMitosisIC505H-pyrido[32-b]pyrrolizin-5-onePharmacology010405 organic chemistryChemistryDrug Discovery3003 Pharmaceutical ScienceOrganic Chemistry5H-pyrido[3ApoptosiTripentoneCancerBiological activityAntitumorGeneral MedicineHCT116 Cellsmedicine.disease0104 chemical sciencesCell cultureApoptosisMCF-7 CellsCancer researchCaco-2 CellsDrug Screening Assays Antitumor

description

Abstract Pyrrolizinones represent an interesting class of compounds with varied degrees of structural complexity and pharmacological activity. Among these, 9H-pyrido[2,3-b]pyrrolizin-9-one, tripentone analogs, recently reported by us, showed significant antiproliferative activity against human tumor cell lines, inducing apoptosis and not affecting viability of Caco-2 differentiated in normal intestinal-like cells. Considering their interesting biological activity, their 5H-pyrido[3,2-b]pyrrolizin-5-one analogs were efficiently synthesized in good to excellent yields (61–91%). All tripentone derivatives were tested to assess their cytotoxicity against two human tumor cell lines, HCT-116 (human colorectal carcinoma) and MCF-7 (human breast cancer). The most active derivatives, with IC50 ranging from 0.11 to 16.11 μM, did not affect viability of Caco-2 differentiated in normal intestinal-like cells, suggesting tumor cells as the main target of their cytotoxic action. The same compounds, further investigated, showed that they did not exert necrotic effects, while induced a clear shift of viable cells towards early apoptosis confining the cells in the mitotic phases.

yearjournalcountryeditionlanguage
2018-01-01European Journal of Medicinal Chemistry
https://doi.org/10.1016/j.ejmech.2018.09.017