Utilization of cyanopyridine in design and synthesis of first-in-class anticancer dual acting PIM-1 kinase/HDAC inhibitors

Discovery of new cyanopyridine/chalcone hybrids as dual inhibitors of EGFR/BRAFV600E with promising antiproliferative properties

“…The key intermediates 3‐cyano‐4,6‐bis(phenyl)‐pyridones 7a–c were prepared in a one‐pot, four‐component reaction without any solvent by the direct stirring of equimolar amounts of the appropriate substituted benzaldehydes 2c, 2d , or 2h , substituted acetophenones 5a, 5b ethyl cyanoacetate, and ammonium acetate at 110 o C for 10–15 min to give the target compounds in excellent yield. [ 30 ] It is worth noting that carrying out this reaction in two steps, first by condensation of the appropriate benzaldehydes with acetophenones in the presence of ethanolic sodium hydroxide to yield chalcones, and then by treating the produced chalcones with ethyl cyanoacetate and excess ammonium acetate in ethanol, gave a poor yield and was time‐consuming. [ 22,28 ] 3‐Cyano‐4,6‐bis(phenyl)‐pyridones 7a–c were alkylated with the appropriate acetylated chalcones 4a–g using the sodium salt of the precursor cyanopyridones 7a–c (promotes alkylation at the nitrogen atom), and carrying out the reaction in an ion‐solvating polar aprotic solvent (DMSO) under inert atmosphere were expected to increase the yield of N‐alkylated hybrids 8–20 .…”

“…There is a great deal of interest in these compounds' anticancer activities because of the various types of biological targets they may interfere with, for example, tubulin, [ 25 ] Survivin protein, [ 26,27 ] PIM‐1 Kinase, [ 28,29 ] and HDAC. [ 30 ] 3‐cyano‐4‐anilino‐5‐phenylpyridine (compound I , Figure 1) is a cyanopyridine derivative that has been tested as an EGFR kinase inhibitor with an IC 50 of 0.66 μM. [ 31 ] Vemurafenib ( II , Figure 1) (Zelboraf®) is a pyridine derivative that has been approved by the FDA for the treatment of late‐stage melanoma.…”

Nicotinonitrile as an essential scaffold in medicinal chemistry: an updated review (2015– present)

“…Hybrid 26 also showed obvious apoptosis-inducing potential in MCF-7 cell lines, causing apoptosis before G1 phase and cell cycle arrest in G2/M phase (Fig. 8) [41].…”

Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives as a new class of EGFRWtand VEGFR-2 inhibitors with apoptotic inducers

“… 2 According to predictions, in 2023, 15 million deaths per year, also cancer represents a real crisis for public health and health systems worldwide. 3 The most common form of cancer worldwide is colorectal cancer (CRC), the second leading cause of death among cancer patients. 4 As a result, current drugs developed based on the single-target single-drug design tend to be less effective in treating heterogeneous, complex, multigenic cancers.…”