Structure-activity relationship studies of indolin-2-one derivatives as vascular endothelial growth factor receptor inhibitors and anticancer agents.

Angiogenesis is a requirement for the growth of cancer cells. The family of vascular endothelial growth factor receptors (VEGFRs) is the main target in metastasis. Indolin-2-one is proved to be an essential scaffold of antiangiogenic drugs. Sunitinib is the first oral indolin-2-one derivative marketed as a VEGFR inhibitor in the treatment of renal cell carcinoma and gastrointestinal stromal tumors. Therefore, novel compounds possessing the scaffold of sunitinib were designed and synthesized by different researchers to improve the anticancer activity, bioavailability, and solubility, and to decrease the toxicity of sunitinib. In this comprehensive review, the structure-activity relationship of different indolin-2-one analogs as VEGFR inhibitors is discussed. It has been observed that the indolin-2-one core is necessary for the inhibition of VEGFRs. It was determined that substitutions at C-3 of the oxindole ring play an important role in their antiangiogenic and anticancer activities.

The Protective Effect of Natural Compounds on Doxorubicin-Induced Cardiotoxicity via Nicotinamide Adenine Dinucleotide Phosphate Oxidase Inhibition.

OBJECTIVES: Doxorubicin (DOX) is widely prescribed for the treatment of several human cancers. Unfortunately, cumulative doses of DOX are the main cause of myocardial dysfunction. Although preclinical and pharmaceutical studies were performed to investigate the potential of natural compounds in minimizing DOX toxicity, a comprehensive review of them is not available. This review can help the researchers for an effective search strategy. KEY FINDINGS: Oxidative stress and p53 play an important role in DOX-associated cardiotoxicity. DOX activates nicotinamide adenine dinucleotide phosphate NADPH oxidase (NOX) in the heart, resulting in excessive reactive oxygen species that can induce cardiomyocyte apoptosis through phosphorylation of p53, DNA damage and/or mitogen-activated protein kinases-mediated cardiomyocyte apoptosis. Although a few chemical drugs with high efficacy are administered along with DOX to prevent or more likely to reduce cardiovascular toxicity, their use is often limited by additional side effects. Recently, attention has been drawn to natural compounds that prevent DOX cardiotoxicity. This review focuses on some of the natural bioactive compounds with potential therapeutic efficacy against DOX-induced cardiotoxicity (DIC). SUMMARY: Some natural compounds, especially flavonols, flavonoids and proanthocyanidins, have the most protective effects against DIC by forming stable radicals and preventing the assembly of the NOX subunits.

Flavonoids, the compounds with anti-inflammatory and immunomodulatory properties, as promising tools in multiple sclerosis (MS) therapy: A systematic review of preclinical evidence.

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, are diseases resulting in neurological disabilities that are regarded as chronic, inflammatory, and autoimmune diseases of central nervous system (CNS). In this respect, the use of anti-inflammatory compounds including flavonoids, polyphenolic compounds abundantly found in vegetables and fruits, has proposed to combat MS to dampen the inflammation and thereby ameliorating the disease severity. The objective of this study was to clarify the probable therapeutic effect of flavonoids for treatment of MS. Therefore, only English published articles that reported the therapeutic effect of flavonoids alone or in combination with other anti-MS therapeutic agents on MS, were selected by searching scientific electronic databases including PubMed, Scopus and Web of Science. Evaluation of the selected researches (686) showed that a total of 13 studies were suitable to be included in this systematic review. Interestingly, all of the studies (11 studies concerning EAE and 2 studies concerning MS) reported positive outcomes for the therapeutic effect of flavonoids on EAE and MS. All flavonoid compounds which are mentioned herein could successfully decrease the maximum clinical score of EAE, which is particularly connected to the anti-inflammatory property of these compounds. The literature review clearly discloses that flavonoids alone or in combination with other anti-MS therapeutic agents can pave the way for improving MS therapeutic strategies.

The natural phenolic compounds as modulators of NADPH oxidases in hypertension.

BACKGROUND: Hypertension is a major public health problem worldwide. It is an important risk factor for other cardiovascular diseases such as coronary artery disease, stroke, heart failure, atrial fibrillation, peripheral vascular disease, chronic kidney disease, and atherosclerosis. PURPOSE: There is strong evidence that excess ROS-derived NADPH oxidase (NOX) is an important agent in hypertension. It augments blood pressure in the presence of other pro-hypertensive factors such as angiotensin II (Ang II), an important and potent regulator of cardiovascular NADPH oxidase, activates NOX via AT1 receptors. NADPH oxidase, a multi-subunit complex enzyme, is considered as a key source of ROS production in the vasculature. The activation of this enzyme is needed for assembling Rac-1, p40phox, p47phox and p67phox subunits. Since, hypertensive patients need to control blood pressure for their entire life and because drugs and other chemicals often induce adverse effects, the use of natural phenolic compounds which are less toxic and potentially beneficial may be good avenues of addition research in our understand of the underlying mechanism involved in hypertension. This review focused on several natural phenolic compounds as berberine, thymoquinone, catechin, celastrol, apocynin, resveratrol, curcumin, hesperidine and G-hesperidine, and quercetin which are NOX inhibitors. In addition, structure activity relationship of these compounds eventually as the most inhibitors was discussed. METHODS: This comprehensive review is based on pertinent papers by a selective search using relevant keywords that was collected using online search engines and databases such as ScienceDirect, Scopus and PubMed. The literature mainly focusing on natural products with therapeutic efficacies against hypertension via experimental models both in vitro and in vivo was identified. RESULTS: It has been observed that these natural compounds prevent NADPH oxidase expression and ROS production while increasing NO bioavailability. It have been reported that they improve hypertension due to formation of a stable radical with ROS-derived NADPH oxidase and preventing the assembly of NOX subunites. CONCLUSION: It is clear that natural phenolic compounds have some potential inhibitory effect on NADPH oxidase activity. In comparison to other phenolic plant compounds, the structural variability of the flavonoids should off different impacts on oxidative stress in hypertension including inhibition of nadph oxidase and direct scavenging of free radicals.