Pyrazolo[3,4‐d]pyrimidine scaffold: A review on synthetic approaches and EGFR and VEGFR inhibitory activities

Abstract

The pyrazolo[3,4‐d]pyrimidine core has received a lot of interest from the medicinal chemistry community as a promising framework for drug design and discovery. It is an isostere of the adenine ring of adenosine triphosphate, which allows it to mimic kinase active site hinge region binding contacts. This scaffold has a wide pharmacological and biological value, one of which is as an anticancer agent. Many successful anticancer medicines have been designed and synthesized using pyrazolo[3,4‐d]pyrimidine as a key pharmacophore. The main synthetic routes of pyrazolo[3,4‐d]pyrimidines as well as their recent developments as promising anticancer agents acting as endothelial growth factor receptors and vascular endothelial growth factor receptor inhibitors, published in the time frame from 1999 to 2022, are summarized in this review to set the direction for the design and synthesis of novel pyrazolo[3,4‐d]pyrimidine derivatives for clinical deployment in cancer treatment.

Medicinal attributes of thienopyrimidine scaffolds incorporating the aryl urea motif as potential anticancer candidates via VEGFR inhibition

“…Then the cyclization of compound I with a suitable reagent either by refluxing with triethylamine (TEA) and acetic anhydride [111] or formamidine acetate in the presence of dimethylformamide (DMF) [82] or refluxing with acetic acid [28] yielded the corresponding thienopyrimidone derivative II. Then, the chloro derivative as a key intermediate III was obtained by refluxing the thienopyrimidone II with POCl 3 .…”

“…[23][24][25] 1.2 | Epidemiology One in every six deaths worldwide is due to cancer, [26] ranking this disease as the second most common cause of mortality globally, accounting for millions of deaths each year. [27,28] The incidence and mortality rates of cancers were calculated by the International Agency for Research on Cancer. In a back flash for 2012, there were around 1.8 million new lung cancer cases and 1.6 million deaths due to lung cancer as the leading cause of morbidity and mortality among various cancers during this year according to the Global Cancer Observatory (GLOBOCAN).…”

Discovery of pyrazolopyrimidines that selectively inhibit CSF-1R kinase by iterative design, synthesis and screening against glioblastoma cells

“…By exploring the chemical diversity surrounding the pyrazolo[3,4- d ]pyrimidine scaffold—a versatile adenine analogue that can be constructed through a multitude of synthetic strategies— 8,9 many labs including ours have demonstrated the potential to identify a wide range of bioactive agents, including inhibitors of protein, lipid and atypical kinases. 10 The BTK inhibitor ibrutinib (top 3 best-selling oncology drug of 2022), first approved for the treatment of B-cell lymphomas in 2013 and later for various other disorders, 11 is the best exemplar of the potential of the pyrazolo[3,4- d ]pyrimidine scaffold for the development of anticancer kinase inhibitors.…”