Pharmacokinetics, Tissue Distribution, and Druggability Prediction of the Natural Anticancer Active Compound Cytisine <i>N</i>-Isoflavones Combined with Computer Simulation

Abstract

Cytisine N-methylene-(5,7-dihydroxy-4'-methoxy)-isoflavone (CNF2) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides. Preliminary pharmacodynamic studies demonstrated its activity in inhibiting breast cancer cell metastasis.This study examined the pharmacokinetics, absolute bioavailability, and tissue distribution of CNF2 in rats, and combined computer-aided technology to predict the druggability of CNF2.The binding site of CNF2 and the breast cancer target HER2 were examined with molecular docking technology. Next, ACD/Percepta software was used to predict the druggability of CNF2 based on the quantitative structure-activity relationship (QSAR). Finally, a simple and effective high-performance liquid chromatography (HPLC) method was used to determine plasma pharmacokinetics and tissue distribution of CNF2 in rats. Prediction and experimental results show that compared with the positive control HER2 inhibitor SYR127063, CNF2 has a stronger binding affinity with HER2, suggesting that its efficacy is stronger; and the structure of CNF2 complies with the Lipinski's Rule of Five and has good drug-likeness. The residence time of CNF2 in rats is less than 4 hours, and the metabolic rate is relatively fast; But the absolute bioavailability of CNF2 in rats was 6.6%, mainly distributed in the stomach, intestine, and lung tissues, where the CNF2 contents were 401.20 μg/g, 144.01 μg/g, and 245.82 μg/g, respectively. This study constructed rapid screening and preliminary evaluation of active compounds, which provided important references for the development and further research of such compounds.

Mechanism of Neural Regeneration Induced by Natural Product LY01 in the 5×FAD Mouse Model of Alzheimer’s Disease

“…Flavones have many functions. They are a strong antioxidants whose capacities are more than 10 times that of vitamin E. They effectively remove oxygen free radicals in the body ( Popovic et al, 2019 ), prevent cell degeneration and aging, and prevent cancer ( Mazewski et al, 2018 ; Chen et al, 2020 ); they also improve blood circulation and lower cholesterol ( Singh et al, 2018 ), inhibit the exudation of inflammatory enzymes, promote wound healing, and relieve pain ( Shoaib et al, 2019 ). Isoflavone is a flavonoid that mainly exists in leguminous plants.…”

Current Systemic Treatment Options in Metastatic Urothelial Carcinoma after Progression on Checkpoint Inhibition Therapy—A Systemic Review Combined with Single-Group Meta-Analysis of Three Studies Testing Enfortumab Vedotin

“…A high expression of HER2 is significantly associated with aggressive disease and poor prognosis [87,88]. New data from a phase II study testing the ADC RC48 (Disitamab Vedotin) targeting HER2 in heavily pretreated HER2 positive mUC was published in October 2020 by Sheng et al [89]. Of the patients, 18.6% had received CPI therapy before study inclusion.…”

Genus Sophora: a comprehensive review on secondary chemical metabolites and their biological aspects from past achievements to future perspectives

“…The anticancer property of a derivative of matrine 246 was explored (Zhou et al 2019). The activity of N-methyl cytisine ( 268 ) in inhibiting breast cancer cell metastasis was previously demonstrated (Chen et al 2020a ).…”

“…The degree of unsaturation in the delta-lactam ring of these lupin alkaloids was necessary to enhibit pinewood nematodes (Ismail et al 2020 ; Ma et al 2020b ; Zhang et al 2020a ). The crude fraction containing cytisine-type alkaloids; N-methyl cytosine ( 268 ) and anagyrine ( 273 ) was more active against the nematodes than the lupin-type alkaloids; sophocarpine ( 235 ), matrine ( 246 ) (Wang et al 2019a ; Chen et al 2020a ; Huang and Xu 2020a ; Ma et al 2020b ).…”