Synthesis of new pyrazolo[3,4‐d]pyrimidine derivatives and evaluation of their anti‐inflammatory and anticancer activities

Abstract

This study reports the synthesis of two series of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to piperazine moiety through different amide linkages. The newly synthesized compounds were evaluated for anticancer activity against four cell lines (MDA-MB-231, MCF-7, SF-268, B16F-10) and cyclooxygenase (COX-2) protein expression inhibition in lipopolysaccharide (LPS)-activated rat monocytes. The results revealed that most of the synthesized compounds showed moderate-to-high cytotoxic activity against at least one cell line, with compound 10b being the most active against all used cell lines (IC values 5.5-11 μg/ml) comparable to cisplatin. In addition, six of these compounds (7b, 10a-d, and 12c) demonstrated inhibition of LPS-induced COX-2 protein expression at low concentration (25 μg/ml) as compared to the control non-stimulated cells and showed a COX-2 selectivity index range comparable to diclofenac sodium. The overall results indicate that many of these pyrazolopyrimidine derivatives possess in vitro anti-inflammatory and anticancer activities at varying doses, and the most active compounds will be subjected to in vivo pharmacological evaluation.

In Vitro and In Vivo Evaluation of the Anticancer and Anti-inflammatory Activities of 2-Himachelen-7-ol isolated from Cedrus Libani

“…Sk-OV-3 cells, however, were shown to be resistant against both 7-HC and Cisplatin treatment (IC 50 >100 µg/mL). The IC 50 values of Cisplatin on the same cancer cell lines are in agreement with the literature 26,27 . In an attempt to achieve an improved therapeutic outcome, all 4 cell lines were subjected to a combination of 7-HC and the conventional antineoplastic drug Cisplatin (Table 3).…”

“…The experiment was conducted in accordance with the internationally accepted principles set by the Office of Laboratory Animal Welfare (NIH, PHS Policy on Human Care and Use of Laboratory Animals, USA 2015) and approved by the Animal Ethical Committee at the Lebanese American University. Isolation of fresh peripheral blood mononuclear cells (PBMCs), consisting of monocytes and lymphocytes, was performed as previously described 26 from blood samples of healthy young male Sprague Dawley rats of (6 weeks age; weighing 250 g) and pretreated with EDTA. EDTA-treated blood (4 mM) was diluted with an equal sterile volume of warm PBS, and centrifuged over Ficoll.…”

Design, Synthesis, and Anticancer Screening for Repurposed Pyrazolo[3,4-d]pyrimidine Derivatives on Four Mammalian Cancer Cell Lines

“…The synthetic procedure of the target compounds was done according to reported procedures [ 5 , 10 , 33 ], resulting in the new unreported compounds 5 and 7, and is available in the Supplementary Materials .…”

“… Chemical structure of previously reported compounds ( A – C ) [ 10 ] as a scaffold for the design of the newly synthesized compounds ( 5 – 7 ). …”

“…Pyrazolopyrimidine modulates many signal pathways that regulate cell proliferation, growth, and apoptosis [9]. Furthermore, the abovementioned findings led to the design and synthesis of a group of compounds that comprise the pyrazolo [3,4-d]pyrimidine scaffold linked to a piperazine moiety, bearing different aromatic nuclei through different amide linkages (compounds of the general formulas B and C; Figure 1), as well as to tests of their anticancer activity [10]. Finally, further screening of literature revealed that the introduction of a 3,4dimethoxybenzylidene moiety to the hydrazine group at the 4-position of the abovementioned nucleus resulted in a new compound (6; Figure 1): this was capable of inhibiting BCR-ABL tyrosine kinase, an enzyme highly implicated in cell proliferation leading to the development of tumours.…”