Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation

Abstract

Novel symmetrical bis-pyrrolo[2,3-d]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-d]pyrimidine monomer 5f with 4,4′-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC50 = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-d]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.

Synthesis and characterization of thiophene-derived palladium(ii) complex immobilized on FSM-16 and its application in the novel synthesis of 7-(aryl)-7,12-dihydro-6H-indeno[1,2,4]triazolo[1,5-a]pyrimidine-6-one derivatives

“…Triazolo pyrimidines have captured the attention of medicinal chemists owing to their wide variety of applications in medicinal chemistry and biochemistry. 53–56…”

“…Triazolo pyrimidines have captured the attention of medicinal chemists owing to their wide variety of applications in medicinal chemistry and biochemistry. [53][54][55][56] In recent years, multi-component reactions containing 1,3indanedione have been successfully developed to synthesize spiro heterocycles, spirocycles, and fused heterocycles. [57][58][59][60] The fused heterocycles are containing the 1,3-indanedione structure from important medicinal and biological frameworks.…”

Design, synthesis, in vitro anticancer, molecular docking and SAR studies of new series of pyrrolo[2,3-d]pyrimidine derivatives

“…As reported in the GLOBOCAN 2020, female breast cancer (with around 2.3 million new cases, 11.7%) surpassed lung tumor (11.4%) as the most commonly diagnosed cancer, followed by colorectal (10.0%), prostate (7.3%) [ 3 ]. By 2030, it is predicted that pancreatic cancer will be in the second stand of cancer-related death after lung tumors [ 4 ].…”

“…The pyrrolo[2,3- d ]pyrimidine derivatives have an important place amongst the pyrrolopyrimidine compounds with various biological properties such as antibacterial [ 17 ], anti-diabetic agents [ 18 , 19 ], antiviral [ 20 , 21 ], anti-inflammatory [ 22 , 23 ], anti-hypertensive activity [ 24 ], anti-protozoal activity [ 25 ], and exhibited strong anticancer activity that serves as an efficient tool for DNA interaction [ 4 , 16 , 26 , 27 ].…”