A Series of Ferrocene-Containing Pyrazolo[1,5-a]pyrimidines Induce a Strong Antiproliferative Effect against Oral Cancer Cells

Abstract

Bio-organometallic agents confer superior physicochemical profiles inaccessible to purely organic molecules. As current chemotherapeutic regimes are maligned by the toxicity and chemoresistance of cisplatin and carboplatin, the development of an arsenal of metallodrugs becomes indispensable. Metallocenes such as ferrociphenols, JAHA, and ferrocene-labeled estradiol exhibit potent anticancer profiles. Oral squamous cell carcinomas are shown to be an excellent model to assess the impact of ferrocene-based pyrazolopyrimidines (FPPs) as chemotherapeutic agents. We show here synthesis and preliminary mechanistic investigations of FPPs in the CAL 27 cell line. The results established that some of the FPPs like 4u display strong antiproliferative behavior selectively against cisplatin-resistant oral cancer cells with an IC 50 value of 7.49 μM. It was also found to activate tumor pyruvate kinase M2 (PKM2), a critical metabolic conduit in cancer. Furthermore, 4u induced apoptosis in cells and arrested cell growth in the S-phase of the cell cycle. In silico studies established that the molecule binds at the DASA-58 binding site of PKM2.

Imidazopyrimidine: from a relatively exotic scaffold to an evolving structural motif in drug discovery

“…1]. 1 In addition, interest in other fused heterocyclic medicines such as triazolopyrimidine, 6 imidazopyridines, 7 and pyrazolopyrimidines 8 as anticancer agents has also increased. Imidazopyrimidine is a bioisostere of indoles and purine bases (adenine and guanine) and is used in a wide range of biological activities, 9 including anti-inflammatory, anti-tumor, and p38 mitogen kinase protein inhibitors.…”