Synthesis and Biological Evaluation of 2,4,6‐Functionalized Derivatives of Pyrido[2,3‐d]pyrimidines as Cytotoxic Agents and Apoptosis Inducers

Abstract

In the search for new derivatives with anticancer activity that are able to induce a selective pro-apoptotic mechanism in cancer cells, we have designed, synthesized, and evaluated a series of new 2-(alkylsulfanyl)-N-alkylpyrido[2,3-d]pyrimidine-4-amine derivatives as cytotoxic and apoptosis inducers. The potential antitumor activity of the compounds was evaluated in vitro by examining their cytotoxic effects against human breast, colon, and bladder cancer-cell lines. The IC(50)values of the compounds that showed cytotoxic activity were calculated. The cytotoxic compounds were then tested for their ability to induce caspase-3 activation and nuclear-chromatin degradation. Some compounds, such as 6c, 6d, 6e, 6j, 6o, and 6p, show significant in-vitro cytotoxicity in at least two of the three tested cell lines, induced apoptosis, and also produced a rapid dose-dependent increase in the caspase-3 level in some of the cell lines tested. In order to test the selectivity of the compounds, two non-tumoral human cell lines were used. Several compounds of the did not show cytotoxicity in these cell lines.

Synthesis of Pyridotriazolopyrimidines as Antitumor Agents

“…Pyrido[2,3‐ d ]pyrimidines exhibited antitumor activity that may be attributed to inhibition of cyclin‐dependent kinase , check point kinase , or mammalian target of rapamycin . Also, many derivatives having pyrido[2,3‐d]pyrimidine core were found to be apoptosis inducers and have anti cell proliferative activity in different solid tumors and leukemia cell lines . Based on these reports and in continuation of our previous work in synthesis of bioactive heterocyclic compounds , herein, we are interested in the synthesis of new series of pyrido[2,3‐ d ]\[1,2,4]triazolo[4,3‐ a ]pyrimidinones 7a , 7b , 7c , 7d , 7e , 7f , 7g , 8 , 9 , 10 , 11 and 15a , 15b , 15c , 15d , 15e , 15f , 15g , 15h , 15i , 15j , 15k , 15l , 15m hoping that the combination of the triazolopyrimidine and pyridopyrimidine scaffolds would produce enhanced antitumor effects.…”

Synthesis and Anticancer Perspective of Pyridopyrimidine Scaffold - An Overview

“…Mohamed Fare et al, [6] have documented pyrido [2,3-d] pyrimidines as antineoplastic agents which can be assigned to the CDK inhibition, [14] rapamycin mammalian target [15], or kinase checkpoint [16]. Further, some of the pyridopyrimidine derivatives were also reported to induce cell apoptosis in various leukemia cell lines and solid tumors [17][18][19].…”

“…Hala B et al, [16] stated pyrido [2,3-d] pyrimidines and fused [1,2,4]triazolo[4,3-a]pyrimidine derivatives, which were reported for anti-tumour activity [14][15][16][17][18][19][20][21][22][23][24][25]. These two groups upon combination results in the formation of tricyclic ring system containing pyridine, triazole and pyrimidines (i.e pyrido [2,3-d [1,2,4] triazolo [4,3-a] pyrimidine) and the resulting impact on the biological activities are delighted [26][27][28][29][30][31][32].…”

Kinase Inhibitors of Novel Pyridopyrimidinone Candidates: Synthesis and In Vitro Anticancer Properties

“…e pyridopyrimidine compounds are a group of fused heterocycles that possess various pharmacological applications as antitumor, topoisomerase I inhibitor, adenosine kinase inhibitor, growth regulator, antihepatitis C virus, antiinflammatory, antileishmanial, antiviral, antimicrobial, anticonvulsant, antimycobacterial, CNS depressant, antihypertensive, antiallergic, diuretic, tyrosine kinase inhibitor, and calcium channel antagonist [7][8][9][10][11][12][13][14][15][16]. Among them, pyrido [2,3-d] pyrimidin-4-ones (A-C) were found to lower cell proliferation in various cancer cell lines through inhibition of various kinases, e.g., TKs, PI3K, and CDK4/6 ( Figure 1) [17][18][19]. In continuation of our earlier studies that involved synthesis of different other substituted pyridopyrimidine compounds [20][21][22] and based on the structural features of pyrido [2,3-d]pyrimidine, this study is designed to synthesize various groups containing different substituents in the phenyl ring at position 5 of the parent compound pyrido [2,3-d] pyrimidinone to further improve the SAR-relationship for their cytotoxicity and also for their inhibitory activity against TKs, CDK4/6, and PI3K enzymes.…”