Expanding the Diversity at the C-4 Position of Pyrido[2,3-d]pyrimidin-7(8H)-ones to Achieve Biological Activity against ZAP-70

Abstract

Pyrido[2,3-d]pyrimidin-7(8H)-ones have attracted widespread interest due to their similarity with nitrogenous bases found in DNA and RNA and their potential applicability as tyrosine kinase inhibitors. Such structures, presenting up to five diversity centers, have allowed the synthesis of a wide range of differently substituted compounds; however, the diversity at the C4 position has mostly been limited to a few substituents. In this paper, a general synthetic methodology for the synthesis of 4-substituted-2-(phenylamino)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones is described. By using cross-coupling reactions, such as Ullmann, Buchwald–Hartwig, Suzuki–Miyaura, or Sonogashira reactions, catalyzed by Cu or Pd, we were able to describe new potential biologically active compounds. The resulting pyrido[2,3-d]pyrimidin-7(8H)-ones include N-alkyl, N-aryl, O-aryl, S-aryl, aryl, and arylethynyl substituents at C4, which have never been explored in connection with the biological activity of such heterocycles as tyrosine kinase inhibitors, in particular as ZAP-70 inhibitors.

Autocatalytic photoinduced oxidative dehydrogenation of pyrido[2,3-d]pyrimidin-7(8H)-ones: synthesis of C5–C6 unsaturated systems with concomitant formation of a long-lived radical

“…1), such as the one that starts from α,β-unsaturated esters (3). Thus, 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridin-3-carbonitriles (5) are obtained by the reaction of an α,β-unsaturated ester (3) and malononitrile (4) in NaOMe/MeOH.…”

“…Our research group has been actively working in the field of Tyrosine Kinase Inhibitors (TKIs) with the aim of developing drug candidates against diverse types of cancers such as breakpoint cluster region protein (BCR) kinase inhibitors for B lymphoid malignancies, 1 discoidin domain-containing receptor 2 (DDR2) inhibitors for the treatment of lung cancer, 2 MAP kinase interacting kinase (MNK1/2) inhibitors for the treatment of breast or prostate cancer, 3 zeta-chain-associated protein kinase 70 kDa (ZAP-70) inhibitors, 4 and more recently a promising candidate for the treatment of pancreatic cancer (unpublished results).…”