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

Andrea Bistrović Popov,Petra Grbčić,Sandra Kraljević Pavelić,Krešimir Pavelić,Robert Vianelo,Silvana Raić-Malić,Mirela Sedić

doi:10.3390/molecules26113334

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.

Highlights

We previously found that bis-pyrrolo[2,3-d]pyrimidine derivatives exhibited potent antiproliferative effect on pancreatic carcinoma (CFPAC-1) cells [45], design strategy led to synthesis of a symmetric series of bis-purines and regioisomeric bis-pyrrolo[2,3d]pyrimidines in which chlorine, amino and cyclic amino groups were introduced at
To demonstrate the necessity to employ the metal catalyst in the Cu(I)catalyzed azide-alkyne cycloaddition (CuAAC) reaction, we have initially investigated the uncatalyzed conversion between model azide m2 and neutral model alkyne m10, which proceeds in accordance with Figure 3
Ultrasound-assisted reactions led to the synthesis of exclusively symmetrical bis-heterocycles with improved yield after 1.5 h

Summary

Introduction

Cancer, defined as uncontrolled, rapid and pathological proliferation of cells, is the second leading cause of death, with more than 18 million cases worldwide annually [1]. Pancreatic cancer is predicted to become the second cause of cancer-related deaths by. 2030, behind lung cancer [2]. Pancreatic ductal adenocarcinoma is the most common pancreatic cancer type, accounting for more than 90% of cases with a five-year survival rate of less than 9% [3,4]. Current therapy suffers from major limitations due to severe side-effects and multidrug resistance, thereby a continued search to find new and safer anticancer drugs and innovate the development of new cancer treatments are required [5,6]

Methods

Results

Conclusion