6533b7d8fe1ef96bd126a2cc
RESEARCH PRODUCT
Insight on pyrimido[5,4-g]indolizine and pyrimido[4,5-c]pyrrolo[1,2-a]azepine systems as promising photosensitizers on malignant cells
Marilia BarrecaAngela Maria IngarraMaria Valeria RaimondiVirginia SpanòMichele De FrancoLuca MenilliValentina GandinGiorgia MioloPaola BarrajaAlessandra Montalbanosubject
PharmacologyMDA-MB-231Triple negative human breast cancerOrganic ChemistryPhototoxic activityIndolizinesAntineoplastic AgentsApoptosisTriple Negative Breast Neoplasms4-g]indolizinespyrimido[4General MedicineAzepinespyrimido[54-g]indolizinespyrimido[45-c]pyrrolo[12-a]azepinesTriple negative human breast cancerMDA-MB-231Photosensitizing agentsPhototoxic activitypyrimido[5Photosensitizing agents5-c]pyrrolo[1pyrimido[45-c]pyrrolo[12-a]azepinesCell Line Tumor2-a]azepinesTriple negative human breast cancerMDA-MB-231Photosensitizing agentsPhototoxic activityDrug DiscoveryHumanspyrimido[54-g]indolizinesdescription
Searching for new small molecules as photosensitizing agents, we have developed a class of twenty-five pyrimido[5,4-g]indolizine and pyrimido[4,5-c]pyrrolo[1,2-a]azepines with a good substitution pattern defining a versatile synthetic pathway to approach the title ring system. All compounds were evaluated for their photocytotoxicity on a triple negative human breast cancer cell line (MDA-MB-231) in the dark and under UVA light (2.0 J/cm2). The most effective compounds exhibited a photoantiproliferative activity with IC50 values up to nanomolar ranges. Interestingly, these new developed compounds showed high selectivity towards cancerous cells with respect to non-cancerous ones. Moreover, four representative derivatives demonstrated to be phototoxic also against an additional human HER2 positive breast cancer cell line (HCC1954), and against the HER2 positive vesical cancer cell line (T24) harboring Hras mutation. Mechanistic studies performed in triple negative MDA-MB-231 cancer cells revealed the ability of the compounds to increase reactive oxygen species (ROS) production and to induce a thiol redox stress, thus triggering cancer cell death through apoptosis. Apoptotic cell death was also induced in highly aggressive and metastatic HER2 positive Hras mutated T24-treated bladder cancer cells. Overall, our data confirm that these new small photosensitizing agents may represent very promising candidates for phototherapy application against highly aggressive and resistant cancers.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2022-03-04 |