New tricyclic systems as photosensitizers towards triple negative breast cancer cells.

Nineteen pyrrolo[1,2-h][1,7]naphthyridinones and pyrido[2,3-c]pyrrolo[1,2-a]azepinones were synthesized as new tricyclic systems in which the pyridine ring is annelated to the 6,7-dihydroindolizin-8(5H)-one and 5,6,7,8-tetrahydro-9H-pyrrole[1,2-a]azepine-9-one moieties to obtain potential photosensitizing agents. They were tested for their photoantiproliferative activity on a triple-negative breast cancer cell line, MDA-MB-231, in the dark and under UVA light (2.0 J/cm2). We demonstrated that their toxicity, only when exposed to light, was primarily due to the generation of reactive oxygen species while their photodegradation products were not responsible for their activity. The most active compounds exhibited photocytotoxicity with IC50 values at low micromolar level inducing a decrease in the intracellular content of thiol, thus triggering cancer cell death through apoptosis. All the pyridone derivatives revealed to be pure photosensitizers with preferential photocytotoxic activity towards cancerous over healthy cells. Altogether, the results obtained confirm pyrrolo[1,2-h][1,7]naphthyridinones and pyrido[2,3-c]pyrrolo[1,2-a]azepinones as promising photosensitisers against triple-negative breast cancer.

Insight on pyrimido[5,4-g]indolizine and pyrimido[4,5-c]pyrrolo[1,2-a]azepine systems as promising photosensitizers on malignant cells.

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.

Recent advances in the development of cyclin-dependent kinase 7 inhibitors.

Cyclin dependent kinase 7 (CDK7) plays a double role as it activates several other cyclin dependent kinases and participates to the initiation of transcription. This kinase is overexpressed in various types of tumors. Relatively few selective CDK7 inhibitors have been up to now disclosed. Most of these inhibitors belong to two chemical families: pyrazolopyrimidines and pyrazolotriazines on one side and pyrimidines on another side. They also differ by their molecular mechanism of action. Some are acting as competitive inhibitors and some others are covalent inhibitors. With these tools, the understanding of the potential therapeutic interest of CDK7 inhibitors in cancer is rapidly growing. They display antiproliferative activity against various types of tumors and leukemia and synergies have been identified. Two inhibitors are undergoing clinical testing. The most potent compounds inhibit a large number of cell-lines with IC50 < 200 nM.