Discovery of Pyrido[3′,2′:5,6]thiopyrano[4,3‑d]pyrimidine-Based Antiproliferative Multikinase Inhibitors

• Published in: ACS medicinal chemistry letters Vol. 10; no. 4; pp. 457 - 462
• Main Authors: Salerno, Silvia, Barresi, Elisabetta, García-Argáez, Aída Nelly, Taliani, Sabrina, Simorini, Francesca, Amendola, Giorgio, Tomassi, Stefano, Cosconati, Sandro, Novellino, Ettore, Da Settimo, Federico, Marini, Anna Maria, Dalla Via, Lisa
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.04.2019; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; KDR kinase; multitargeted kinase inhibitors; Pyridothiopyranopyrimidines; antiproliferative activity; VEGF; KINASE INHIBITORS; CANCER; RENAL-CELL CARCINOMA; UPDATE; AGENTS; CYTOTOXICITY; DERIVATIVES; SURFACES
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.8b00499

Protein kinases dysregulation is extremely common in cancer cells, and the development of new agents able to simultaneously target multiple kinase pathways involved in angiogenesis and tumor growth may offer several advantages in the treatment of cancer. Herein we report the discovery of new pyridothiopyranopyrimidine derivatives (2–4) showing high potencies in VEGFR-2 KDR inhibition as well as antiproliferative effect on a panel of human tumor cell lines. Investigation on the selectivity profile of the representative 2-anilino-substituted compounds 3b, 3i, and 3j revealed a multiplicity of kinase targets that should account for the potent antiproliferative effect produced by these pyridothiopyranopyrimidine derivatives.