Synthesis and Evaluation of Anisomelic acid-like Compounds for the Treatment of HPV-Mediated Carcinomas

Abstract

The vast majority of cervical and 75% of oropharyngeal carcinomas are triggered by infection with a type of high-risk oncogenic human papillomavirus (HPV). It is well-known that E6 and E7 oncoproteins are critical for viral-induced cancer, and hence, they represent valuable targets for therapeutic intervention in HPV-mediated cancers. Our earlier research on the cembranoid, anisomelic acid (AA) showed that, AA has the potential to induce apoptosis in HPV cells by the depletion of E6 and E7 oncoproteins. The present study describes the structure-activity relationship and the evaluation of synthetic AA like compounds, i.e simplified cembranoid-like structures, as HPV inhibitors against some papilloma cell lines. Both from experimental and computational results, we observed that these compounds induced apoptosis by the same E6/E7-based mechanism as AA, but at earlier time points, thus being far more effective than AA. Further, the data indicated that only part of the structure of AA is required for the molecular action. Based on these results, we identified some novel and potential compounds for specific treatment of HPV-associated carcinomas.

Anisomeles indica Extracts and Their Constituents Suppress the Protein Expression of ACE2 and TMPRSS2 In Vivo and In Vitro

“…indica is a commonly used medicinal plant in traditional medicine, known for its various pharmacological activities, including anti-HIV, antibacterial, antioxidant, and anticancer properties. It has shown potential in drug development for antiviral and anti-tumor agents [16][17][18][19][46][47][48]. A. indica is rich in various active compounds, such as ovatodiolide, anisomlic acid, and apigenin, all of which have been indicated by studies to possess antiviral effects.…”

In Silico Approaches: A Way to Unveil Novel Therapeutic Drugs for Cervical Cancer Management

“…Senthilkumar and colleagues described ansiomelic acid (AA), a compound isolated from the plant Anisomeles malabarica , as being able to inhibit E6 and E7 protein expression and induce apoptosis in HPV-positive cancer cells. Then, they decided to perform a structure–activity relationship study with several AA analogues to identify potent inhibitors of HPV E6 and E7 oncoproteins [ 37 ]. Molecular docking was used to predict the affinity of 26 AA-derived compounds towards the hydrophobic pocket of the E6 protein (PDB ID: 4GIZ) using AA as control.…”

“…Of these, compounds 4 and 5 ( Figure 2 ) showed the highest docking scores −65.74 Kcal/mol and −63.66 Kcal/mol, respectively, and lower IC 50 values (HPV-positive cell lines, SiHa and HeLa) were observed when compared to AA and other compounds. In addition, they displayed less toxicity towards fibroblasts than commercial drugs and were able to inhibit p53 degradation mediated by the E6 protein, according to the in vitro studies performed [ 37 ].…”