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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
Applying molecular hybridization to design a new class of pyrazolo[3,4-d]pyrimidines as Src inhibitors active in
Salvatore Di Maria1, Raffaele Passannanti1, Federica Poggialini1
1Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy.
Abstract:
Hepatocellular carcinoma (HCC) is the most common type of liver solid tumor and the second leading cause of cancer-related deaths worldwide. Although new treatment options have been recently approved, the development of tumor resistance and the poor prognosis for advanced HCC make the current standard of care unsatisfying. In this scenario, the non-receptor tyrosine kinase (TK) c-Src emerged as a promising target for developing new anti-HCC agents. Our group reported a large library of pyrazolo[3,4-d]pyrimidines active as potent c-Src inhibitors. Starting from these data, we applied a molecular hybridization approach to combine the in-house pyrazolo[3,4-d]pyrimidine SI192 with the approved TK inhibitor (TKI) dasatinib, with the aim of identifying a new generation of Src inhibitors. Enzymatic results prompted us to design second-generation compounds with a better binding profile based on a hit optimization protocol comprised of molecular modeling and on-paper rational design. This investigation led to the identification of a few nanomolar Src inhibitors active toward two HCC cell lines (HepG2 and HUH-7) selected according to their high and low c-Src expression, respectively. In particular, 7e showed an IC50 value of 0.7 nM toward Src and a relevant antiproliferative efficacy on HepG2 cells after 72h (IC50 = 2.47 μM). Furthermore, 7e exhibited a cytotoxic profile better than dasatinib. The ADME profile suggested that 7e deserves further investigation as a promising TKI in cancer therapies. Finally, 7e's ability to inhibit HepG2 cell proliferation, elicit an irreversible cytotoxic effect, arrest cellular migration, and induce apoptotic-mediated cell death was assessed.
Insights
Researchers developed novel pyrazolo[3,4-d]pyrimidine compounds targeting c-Src for hepatocellular carcinoma (HCC). Compound 7e demonstrated potent inhibition and anti-cancer effects, showing promise as a new tyrosine kinase inhibitor (TKI) therapy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) presents a significant global health challenge with limited treatment options for advanced stages.
- Tumor resistance and poor prognosis highlight the need for novel therapeutic strategies.
- The non-receptor tyrosine kinase c-Src is a promising molecular target for anti-HCC drug development.
Purpose of the Study:
- To design and synthesize novel pyrazolo[3,4-d]pyrimidine derivatives as potent c-Src inhibitors.
- To identify new generation tyrosine kinase inhibitors (TKIs) for hepatocellular carcinoma (HCC) treatment.
- To evaluate the efficacy and safety of novel compounds against HCC cell lines.
Main Methods:
- Molecular hybridization of pyrazolo[3,4-d]pyrimidine SI192 with dasatinib.
- Hit optimization using molecular modeling and rational design.
- Enzymatic assays, cell-based assays (HepG2, HUH-7), and ADME profiling.
Main Results:
- Identification of nanomolar c-Src inhibitors, including compound 7e.
- Compound 7e exhibited high potency against c-Src (IC50 = 0.7 nM) and significant antiproliferative effects on HepG2 cells (IC50 = 2.47 μM).
- Compound 7e demonstrated superior cytotoxic profile and favorable ADME properties compared to dasatinib.
Conclusions:
- Compound 7e represents a promising TKI candidate for HCC therapy.
- 7e effectively inhibits HCC cell proliferation, induces apoptosis, and arrests cell migration.
- Further investigation of 7e is warranted for its potential in cancer treatment.
