Synthesis of salicylic acid phenylethyl ester (SAPE) and its implication in immunomodulatory and anticancer roles

Abstract

Salicylic acid phenylethyl ester (SAPE) was synthesized by Zn(OTf)2-catalyzed selective esterification of salicylic acid and phenylethyl alcohol and studied for its role as an immunomodulatory and anticancer agent. Low toxicity and favorable physical, Lipinski-type, and solubility properties were elucidated by ADME-tox studies. Molecular docking of SAPE against COX-2 revealed favorable MolDockscore, rerank score, interaction energy, internal pose energy, and hydrogen bonding as compared to ibuprofen and indomethacin. An average RMSD of ~ 0.13 nm for the docked complex with stable dynamic equilibrium condition was noted during the 20 ns MD simulation. A low band gap predicting a strong binding affinity at the enzyme’s active site was further predicted by DFT analysis. The ester caused a reduction in the percentage of erythrocyte hemolysis and was shown to be non-cytotoxic against human lymphocytes, CaCo-2, and HepG-2 cells by the MTT assay. Moreover, it’s in vitro efficacy in inhibiting COX-2 enzyme under both LPS stimulated intestinal cells and direct sequestration assays was found to be higher than salicylic acid and indomethacin. The anticancer activity of SAPE was tested on the breast cancer cell line MCF-7, and potential efficacy was exhibited in terms of decreased cell viability. Flow cytometry analysis exhibited the arrest of the cell cycle at G1/G0 and S phases, during which induction of autophagic vesicle formation and decrease in mitochondrial membrane potential was observed owing to increased ROS production. Furthermore, at these phases, the onset of apoptosis along with DNA damage was also observed. Pre-treatment with SAPE in colitis-induced Wistar rats displayed low disease activity index and reduction in the extent of intestinal tissue disruption and lipid peroxidation. A marked increase of anti-oxidative enzymes viz., catalase, GGT, and GST, and a decrease of pro-inflammatory cytokines IL-6 and TNF-α in the intestinal tissue extracts of the treated groups was noted. The results of this study have sufficient credence to support that the synthesised ester (SAPE) be considered as an anti-oxidative and anti-inflammatory compound with therapeutic potential for the effective management of cancer.

Biological Activity of Oleanolic Acid Derivatives HIMOXOL and Br-HIMOLID in Breast Cancer Cells Is Mediated by ER and EGFR

“…Moreover, the introduction of the lactone to a compound structure increases anticancer activity [ 68 , 69 ]. Additionally, the introduction of bromine improves lipophilicity and biomedical application [ 70 ], and compound esterification increases water solubility [ 71 ].…”

Estimation of Serum Sialic Acid in the Patients of Type-2 Diabetes Mellitus

“…8 Sialicacid is primarily made up of glycoproteins and glycol lipids found at the membrane of cells. 9 In the acute phase of a reaction, sialic acid is considered a biomarker . 18 The negative charge on renal basement membrane also controlled by sialic acid, so sialic acid consider as one of main regulator of membrane permeability.…”

“…7 As a cofactor, sialic acid is mainly active during acute stages of inflammation or injury, and it acts primarily on cell receptors as a cofactor. 8,9 In the cell membrane, glycoproteins and glycol lipids, which form sialic acid, make up a significant portion of the structure. 10 Endothelial and vascular permeability of sialic acid is controlled by the molecular composition of sialic acid.…”

Pemetrexed–Poly(salicylic acid) Assemblies Reshape Immunosuppressive Tumor Microenvironment for Enhanced Chemo-immunotherapy

“…13,14 Salicylic acid (SA), as the FDA approved antiinflammatory drug, is the functional ingredient of aspirin, which has been reported to restrain the activity of the COX-2/ PGE 2 axis. 9,10,15 Given its side effects limiting potential application in tumor therapy, nanoparticles-based drug delivery systems may be developed for the selective delivery of SA to tumor sites. Nanotherapy platforms have been particularly promising for tumor therapy over two decades.…”

“…Several previous studies have revealed the antitumor effect of COX-2/PGE 2 inhibitors to boost antitumor immunotherapy at high-dose administration. ,, However, one lethal vulnerability is that oral high-dose administration of COX-2/PGE 2 inhibitors can cause gastrointestinal bleeding and cardiac events. , Salicylic acid (SA), as the FDA approved anti-inflammatory drug, is the functional ingredient of aspirin, which has been reported to restrain the activity of the COX-2/PGE 2 axis. ,, Given its side effects limiting potential application in tumor therapy, nanoparticles-based drug delivery systems may be developed for the selective delivery of SA to tumor sites. Nanotherapy platforms have been particularly promising for tumor therapy over two decades.…”