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Discovery of Pyrido[3',2':5,6]thiopyrano[4,3-d]pyrimidine-Based Antiproliferative Multikinase Inhibitors
Silvia Salerno1, Elisabetta Barresi1, Aída Nelly García-Argáez2
1Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Abstract:
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.
Insights
Researchers discovered novel pyridothiopyranopyrimidine compounds that inhibit VEGFR-2 KDR and show potent antiproliferative effects against human tumor cells, offering new cancer treatment strategies.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Dysregulation of protein kinases is a hallmark of cancer.
- Targeting multiple kinase pathways involved in angiogenesis and tumor growth presents a promising therapeutic strategy.
Purpose of the Study:
- To discover and characterize novel pyridothiopyranopyrimidine derivatives as potential anticancer agents.
- To evaluate the inhibitory activity against VEGFR-2 KDR and antiproliferative effects on human tumor cell lines.
Main Methods:
- Synthesis of novel pyridothiopyranopyrimidine derivatives (compounds 2-4).
- In vitro kinase inhibition assays, focusing on VEGFR-2 KDR.
- Antiproliferative assays against a panel of human tumor cell lines.
- Kinase selectivity profiling of lead compounds.
Main Results:
- Compounds 2-4 demonstrated high potency in inhibiting VEGFR-2 KDR.
- These derivatives exhibited significant antiproliferative effects on various human tumor cell lines.
- Selectivity profiling revealed multiple kinase targets for compounds 3b, 3i, and 3j, correlating with their potent anticancer activity.
Conclusions:
- Pyridothiopyranopyrimidine derivatives represent a promising class of compounds for cancer therapy.
- Simultaneous inhibition of multiple kinase targets, including VEGFR-2 KDR, contributes to their potent antiproliferative effects.
- Further investigation of these compounds may lead to the development of novel anticancer drugs.