Design, Synthesis, and Biological Evaluation of a Novel VEGFR-2 Inhibitor Based on a 1,2,5-Oxadiazole-2-Oxide Scaffold with MAPK Signaling Pathway Inhibition

Abstract

Over the past few decades, the development of broad-spectrum anticancer agents with anti-angiogenic activity has witnessed considerable progress. In this study, a new series of pyrazolo[3 ,4-d]pyrimidines based on a phenylfuroxan scaffold were designed, synthesized, and evaluated, in terms of their anticancer activities. NCI-60 cell one-dose screening revealed that compounds 12a–c and 14a had the best MGI%, among the tested compounds. The target fluorinated compound 12b, as the most active one, showed better anticancer activity compared to the reference drug sorafenib, with IC50 values of 11.5, 11.6, and 13 µM against the HepG-2, A2780CP, and MDA-MB-231 cell lines, respectively. Furthermore, compound 12b (IC50 = 0.092 µM) had VEGFR-2-inhibitory activity comparable to that of the standard inhibitor sorafenib (IC50 = 0.049 µM). Furthermore, the ability of compound 12b in modulating MAPK signaling pathways was investigated. It was found to decrease the level of total ERK and its phosphorylated form, as well as leading to the down-regulation of metalloproteinase MMP-9 and the over-expression of p21 and p27, thus leading to subG1 cell-cycle arrest and, thus, the induction of apoptosis. Additionally, compound 12b decreased the rate of wound healing in the absence of serum, in comparison to DMSO-treated cells, providing a significant impact on metastasis inhibition. The quantitative RT-PCR results for E-cadherin and N-cadherin showed lower expression of the neuronal N-cadherin and increased expression of epithelial E-cadherin, indicating the ability of 12b to suppress metastasis. Furthermore, 12b-treated HepG2 cells expressed a low level of anti-apoptotic Bcl-2 and over-expressed proapoptotic Bax genes, respectively. Using the DAF-FM DA fluorescence probe, compound 12b produced NO intracellularly as efficiently as the reference drug JS-K. In silico molecular docking studies showed a structural similarity through an overlay of 12b with sorafenib. Interestingly, the drug-likeness properties of compound 12b met the expectations of Pfizer’s rule for the design of new drug candidates. Therefore, this study presents a novel anticancer lead compound that is worthy of further investigation and activity improvement.

Utilizing Estra-1,3,5,16-Tetraene Scaffold: Design and Synthesis of Nitric Oxide Donors as Chemotherapeutic Resistance Combating Agents in Liver Cancer

“…As illustrated in Scheme 2 , the precursor 2-(( tert -butyldimethylsilyl)oxy)-2-methylpropanal was synthesized as reported [ 31 ] and subjected to aldol condensation with the key intermediates α-hydroxymethylketones 11a , b using LDA to afford the desired cucurbitacin-inspired estra-1,3,5,16-tetraene analogs 12a , b . Then, they underwent deprotection to provide the phenolic derivatives 13a , b , which were coupled with furoxan mesylate [ 16 , 32 ] to afford the target cucurbitacin-inspired estra-1,3,5,16-tetraene furoxan analogs (NO-CIETA) 14a , b .…”

Review on the Significance of Pyrimidine Derivatives as Potent Anti-Angiogenic Vegfr-2 Inhibitors

“…With IC50 values of 11.5, 11.6, and 13 µM, the fluorinated compound 11 showed the strongest cytotoxic activity compared to sorafenib against the HepG-2, A2780CP, and MDA-MB-231 cell lines. In addition, compound 11 showed the highest inhibitory effect against VEGFR-2 compared to sorafenib with IC50 equal to 0.092 versus 0.049 µM for sorafenib (Mahnashi, El-Senduny et al 2022).…”

The current scenario of furoxan hybrids with anticancer potential

“…The furoxan‐azole hybrids also possessed potential antiproliferative activity, and among them, furoxan‐pyrazolo[3,4‐d]pyrimidine hybrid 52 (IC 50 : 11.6–18.6 μ M, MTT assay) was comparable to sorafenib (IC 50 : 10.5–16.6 μ M) against SKOV‐3, A2780, A2780CP, MDA‐MB‐231, and HT‐29 cancer cell lines [74–77]. Mechanistically, hybrid 52 could decrease the level of total ERK and its phosphorylated form and led to the down‐regulation of the metastatic protein metalloproteinase MMP‐9 and the over‐expression of the cell‐cycle inhibitors p21 and p27, arrest of subG1 phase and induction apoptosis [77]. Hence, hybrid 52 was a useful scaffold and was worthy of further investigations.…”