Angiogenesis, the process of formation and recruitment of new blood vessels from pre-existing vessels, plays an important role in the development of cancer. Therefore, the use of antiangiogenic agents is one of the most critical strategies for the treatment of cancer. In addition, the complexity of cancer pathogenicity raises the need for multi-targeting agents. Coumarins are multi-targeting natural agents belonging to the class of benzopyrones. Coumarins have several biological and pharmacological effects, including antimicrobial, antioxidant, anti-inflammation, anticoagulant, anxiolytic, analgesic, and anticancer properties. Several reports have shown that the anticancer effect of coumarins and their derivatives are mediated through targeting angiogenesis by modulating the functions of vascular endothelial growth factor as well as vascular endothelial growth factor receptor 2, which are involved in cancer pathogenesis. In the present review, we focus on the antiangiogenic effects of coumarins and related structure-activity relationships with particular emphasis on cancer.

Isofraxidin (7-hydroxy-6, 8-dimethoxy coumarin) (IF) is a hydroxy coumarin with several biological and pharmacological activities. The plant kingdom is of the most prominent sources of IF, which, among them, Eleutherococcus and Fraxinus are the well-known genera in which IF could be isolated/extracted from their species. Considering the complex pathophysiological mechanisms behind some diseases (e.g., cancer, neurodegenerative diseases, and heart diseases), introducing IF as a potent multi-target agent, which possesses several herbal sources and the multiple methods for isolation/purification/synthesis, along with the unique pharmacokinetic profile and low levels of side effects, could be of great importance. Accordingly, a comprehensive review was done without time limitations until February 2020. IF extraction methods include microwave, mechanochemical, and ultrasound, along with other conventional methods in the presence of semi-polar solvents such as ethyl acetate (EtOAc). In addition to the isolation methods, related synthesis protocols of IF is also of great importance. From the synthesis point of view, benzaldehyde derivatives are widely used as precursors for IF synthesis. Along with the methods of isolation and biosynthesis, IF pharmacokinetic studies showed hopeful in vivo results of its rapid absorption after oral uses, leading to different pharmacological effects. In this regard, IF targets varieties of inflammatory mediators including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), and matrix metalloproteinases (MMPs). thereby indicating anticancer, cardioprotective, and neuroprotective effects. This is the first review on the synthesis, biosynthesis, isolation, and pharmacokinetic and pharmacological properties of IF in combating different diseases.

Since its inception, the coronavirus disease 2019 (COVID-19) pandemic has infected millions of people around the world. Therefore, it is necessary to find effective treatments against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), as it is the viral source of COVID-19. Alkaloids are one of the most widespread plant-derived natural compounds with prominent antiviral effects. Accordingly, these phytochemicals have been promising candidates towards discovering effective treatments for COVID-19. Alkaloids have shown potential anti-SARS-CoV activities via inhibiting pathogenesis-associated targets of the Coronaviridae family that are required for the virus life cycle. In the current study, the chemistry, plant sources, and antiviral effects of alkaloids, as well as their anti-SARS-CoV-2 effect with related mechanisms, are reviewed towards discovering an effective treatment against COVID-19.

Saponins are one of the broadest classes of high-molecular-weight natural compounds, consisting mainly of a non-polar moiety with 27 to 30 carbons and a polar moiety containing sugars attached to the sapogenin structure. Saponins are found in more than 100 plant families as well as found in marine organisms. Saponins have several therapeutic effects, including their administration in the treatment of various cancers. These compounds also reveal noteworthy anti-angiogenesis effects as one of the critical strategies for inhibiting cancer growth and metastasis. In this study, a comprehensive review is performed on electronic databases, including PubMed, Scopus, ScienceDirect, and ProQuest. Accordingly, the structural characteristics of triterpenoid/steroid saponins and their anti-cancer effects were highlighted, focusing on their anti-angiogenic effects and related mechanisms. Consequently, the anti-angiogenic effects of saponins, inhibiting the expression of genes related to vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF-1α) are two main anti-angiogenic mechanisms of triterpenoid and steroidal saponins. The inhibition of inflammatory signaling pathways that stimulate angiogenesis, such as pro-inflammatory cytokines, mitogen-activated protein kinase (MAPKs), and phosphoinositide 3-kinases/protein kinase B (PI3K/Akt), are other anti-angiogenic mechanisms of saponins. Furthermore, the anti-angiogenic and anti-cancer activity of saponins was closely related to the binding site of the sugar moiety, the type and number of their monosaccharide units, as well as the presence of some functional groups in their aglycone structure. Therefore, saponins are suitable candidates for cancer treatment by inhibiting angiogenesis, for which extensive pre-clinical and comprehensive clinical trial studies are recommended.