Chemopreventive Effect on Human Colon Adenocarcinoma Cells of Styrylquinolines: Synthesis, Cytotoxicity, Proapoptotic Effect and Molecular Docking Analysis.

Seven styrylquinolines were synthesized in this study. Two of these styrylquinolines are new and were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620, and normal cells (HaCaT). According to the results, compounds 3a and 3d showed antiproliferative activity in SW480 and SW620 cells, but their effect seemed to be caused by different mechanisms of action. Compound 3a induced apoptosis independent of ROS production, as evidenced by increased levels of caspase 3, and had an immunomodulatory effect, positively regulating the production of different immunological markers in malignant cell lines. In contrast, compound 3d generated a pro-oxidant response and inhibited the growth of cancer cells, probably by another type of cell death other than apoptosis. Molecular docking studies indicated that the most active compound, 3a, could efficiently bind to the proapoptotic human caspases-3 protein, a result that could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. The obtained results suggest that these compounds have chemopreventive potential against CRC, but more studies should be carried out to elucidate the molecular mechanisms of action of each of them in depth.

Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells.

A series of 5-FU-Genistein hybrids were synthesized and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated in human colon adenocarcinoma cells (SW480 and SW620) and non-malignant cell lines (HaCaT and CHO-K1). Hybrid 4a displayed cytotoxicity against SW480 and SW620 cells with IC50 values of 62.73 ± 7.26 µM and 50.58 ± 1.33 µM, respectively; compound 4g induced cytotoxicity in SW620 cells with an IC50 value of 36.84 ± 0.71 µM. These compounds were even more selective than genistein alone, the reference drug (5-FU) and the equimolar mixture of genistein plus 5-FU. In addition, hybrids 4a and 4g induced time- and concentration-dependent antiproliferative activity and cell cycle arrest at the S-phase and G2/M. It was also observed that hybrid 4a induced apoptosis in SW620 cells probably triggered by the extrinsic pathway in response to the activation of p53, as evidenced by the increase in the levels of caspases 3/8 and the tumor suppressor protein (Tp53). Molecular docking studies suggest that the most active compound 4a would bind efficiently to proapoptotic human caspases 3/8 and human Tp53, which in turn could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. On the other hand, molecular dynamics (MD) studies provided strong evidence of the conformational stability of the complex between caspase-3 and hybrid 4a obtained throughout 100 ns all-atom MD simulation. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analyses of the complex with caspase-3 showed that the interaction between the ligand and the target protein is stable. Altogether, the results suggest that the active hybrids, mainly compound 4a, might act by modulating caspase-3 activity in a colorectal cancer model, making it a privileged scaffold that could be used in future investigations.

Uncaria tomentosa (cat's claw): a promising herbal medicine against SARS-CoV-2/ACE-2 junction and SARS-CoV-2 spike protein based on molecular modeling.

COVID-19 is a novel severe acute respiratory syndrome coronavirus. Currently, there is no effective treatment and vaccines seem to be the solution in the future. Virtual screening of potential drugs against the S protein of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) has provided small molecular compounds with a high binding affinity. Unfortunately, most of these drugs do not attach with the binding interface of the receptor-binding domain (RBD)-angiotensin-converting enzyme-2 (ACE-2) complex in host cells. Molecular modeling was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (cat's claw) focusing on the binding interface of the RBD-ACE-2 and the viral spike protein. The in silico approach starts with protein-ligand docking of 26 Cat's claw key components followed by molecular dynamics simulations and re-docked calculations. Finally, we carried out drug-likeness calculations for the most qualified cat's claw components. The structural bioinformatics approaches led to the identification of several bioactive compounds of U. tomentosa with potential therapeutic effect by dual strong interaction with interface of the RBD-ACE-2 and the ACE-2 binding site on SARS-CoV-2 RBD viral spike. In addition, in silico drug-likeness indices for these components were calculated and showed good predicted therapeutic profiles of these phytochemicals found in U. tomentosa (cat's claw). Our findings suggest the potential effectiveness of cat's claw as complementary and/or alternative medicine for COVID-19 treatment.Communicated by Ramaswamy H. Sarma.

The Hydroalcoholic Extract of Uncaria tomentosa (Cat's Claw) Inhibits the Infection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) In Vitro.

The coronavirus disease 2019 (COVID-19) has become a serious problem for public health since it was identified in the province of Wuhan (China) and spread around the world producing high mortality rates and economic losses. Nowadays, the WHO recognizes traditional, complementary, and alternative medicine for treating COVID-19 symptoms. Therefore, we investigated the antiviral potential of the hydroalcoholic extract of Uncaria tomentosa stem bark from Peru against SARS-CoV-2 in vitro. The antiviral activity of U. tomentosa against SARS-CoV-2 in vitro was assessed in Vero E6 cells using cytopathic effect (CPE) and plaque reduction assay. After 48 h of treatment, U. tomentosa showed an inhibition of 92.7% of SARS-CoV-2 at 25.0 µg/mL (p < 0.0001) by plaque reduction assay on Vero E6 cells. In addition, U. tomentosa induced a reduction of 98.6% (p=0.02) and 92.7% (p=0.03) in the CPE caused by SARS-CoV-2 on Vero E6 cells at 25 µg/mL and 12.5 µg/mL, respectively. The EC50 calculated for the U. tomentosa extract by plaque reduction assay was 6.6 µg/mL (4.89-8.85 µg/mL) for a selectivity index of 4.1. The EC50 calculated for the U. tomentosa extract by TCID50 assay was 2.57 µg/mL (1.05-3.75 µg/mL) for a selectivity index of 10.54. These results showed that U. tomentosa, known as cat's claw, has an antiviral effect against SARS-CoV-2, which was observed as a reduction in the viral titer and CPE after 48 h of treatment on Vero E6 cells. Therefore, we hypothesized that U. tomentosa stem bark could be promising in the development of new therapeutic strategies against SARS-CoV-2.

Carvacrol: An In Silico Approach of a Candidate Drug on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR Receptors in the Breast Cancer.

Carvacrol is a phenol monoterpene found in aromatic plants specially in Lamiaceae family, which has been evaluated in an experimental model of breast cancer. However, any proposed mechanism based on its antitumor effect has not been reported. In our previous study, carvacrol showed a protective effect on 7,12-dimethylbenz[α]anthracene- (DMBA-) induced breast cancer in female rats. The main objective in this research was to evaluate by using in silico study the carvacrol on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR receptors involved in breast cancer progression by docking analysis, molecular dynamic, and drug-likeness evaluation. A multilevel computational study to evaluate the antitumor potential of carvacrol focusing on the main targets involved in the breast cancer was carried out. The in silico study starts with protein-ligand docking of carvacrol followed by ligand pathway calculations, molecular dynamic simulations, and molecular mechanics energies combined with the Poisson-Boltzmann (MM/PBSA) calculation of the free energy of binding for carvacrol. As result, the in silico study led to the identification of carvacrol with strong binding affinity on mTOR receptor. Additionally, in silico drug-likeness index for carvacrol showed a good predicted therapeutic profile of druggability. Our findings suggest that mTOR signaling pathway could be responsible for its preventive effect in the breast cancer.

Investigating Potential Inhibitory Effect of Uncaria tomentosa (Cat's Claw) against the Main Protease 3CLpro of SARS-CoV-2 by Molecular Modeling.

COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2. Presently, there is no effective treatment for COVID-19. As part of the worldwide efforts to find efficient therapies and preventions, it has been reported the crystalline structure of the SARS-CoV-2 main protease Mpro (also called 3CLpro) bound to a synthetic inhibitor, which represents a major druggable target. The druggability of Mpro could be used for discovering drugs to treat COVID-19. A multilevel computational study was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (Cat's claw), focusing on the inhibition of Mpro. The in silico approach starts with protein-ligand docking of 26 Cat's claw key components, followed by ligand pathway calculations, molecular dynamics simulations, and MM-GBSA calculation of the free energy of binding for the best docked candidates. The structural bioinformatics approaches led to identification of three bioactive compounds of Uncaria tomentosa (speciophylline, cadambine, and proanthocyanidin B2) with potential therapeutic effects by strong interaction with 3CLpro. Additionally, in silico drug-likeness indices for these components were calculated and showed good predicted therapeutic profiles of these phytochemicals. Our findings suggest the potential effectiveness of Cat's claw as complementary and/or alternative medicine for COVID-19 treatment.

TOCOSH FLOUR (Solanum tuberosum L.): A Toxicological Assessment of Traditional Peruvian Fermented Potatoes.

Potato tocosh is a naturally processed potato for nutritional and curative purposes from traditional Peruvian medicine. The aim of this study was to investigate the acute and sub-acute toxicity of tocosh flour (TF). For sub-acute toxicity, TF was administered orally to rats daily once a day for 28 days at doses of 1000 mg/kg body weight (BW). Animals were observed for general behaviors, mortality, body weight variations, and histological analysis. At the end of treatment, relative organ weights, histopathology, hematological and biochemical parameters were analyzed. For acute toxicity, TF was administered orally to mice at doses of 2000 and 5000 mg/kg BW at a single dose in both sexes. Body weight, mortality, and clinical signs were observed for 14 days after treatment. The results of acute toxicity showed that the median lethal dose (LD50) value of TF is higher than 2000 g/kg BW but less than 5000 mg/Kg BW in mice. Death and toxicological symptoms were not found during the treatment. For sub-acute toxicity, we found that no-observed-adverse-effect levels (NOAEL) of TF in rats up to 1000 g/kg BW. There were statistically significant differences in body weight, and relative organ weight in the stomach and brain. No differences in hematological and biochemical parameters were observed when compared with the control group. For sub-acute toxicity, histopathological studies revealed minor abnormalities in liver and kidney tissues at doses of 5000 mg/Kg. Based on these results, TF is a traditional Peruvian medicine with high safety at up to 1000 mg/kg BW for 28 days in rats.