Mini Reviews in Medicinal Chemistry - Volume 20, Issue 2, 2020

Objective: This mini-review aims to discuss research works about heparanase published in 2016, 2017, 2018 and 2019 and provide a direction for therapy methods targeting heparanase. Patients and Methods: The relevant data were searched by using keywords “heparanase” “function”, “diseases” and “inhibitors” in “PubMed”, “Web of Science” and “China Knowledge Resource Integrated databases (CNKI)”, and a hand-search was done to acquire peer-reviewed articles and reports about heparanase. Results: Except for tumor progression, pathological processes including procoagulant activities, preeclamptic placentas, inflammation and so on are all verified to be associated with heparanase activity. Also, these newly-found functions are closely related to certain cellular activities, including epithelial to Mesenchymal Transition (EMT). Conclusion: It could be concluded that heparanase would be a potential and valuable therapy target.

Natural polysaccharide is a kind of natural macromolecular which can be extracted from plants, fungi, algae, animals, and bacteria. The monosaccharide compositions and glucosidic bonds of polysaccharides from different origins vary substantially. Natural polysaccharides have been shown to possess complex, important and multifaceted biological activities including antitumor, anticoagulant, antioxidative, antiviral, immunomodulatory, antihyperlipidemic and antihepatotoxic activities. Their properties are mainly due to their structural characteristics. It is necessary to develop polysaccharide immunomodulators with potential for preventive or therapeutic action. The present paper summarizes the structural features, immunostimulatory activity and the immunomodulatory mechanisms of natural polysaccharides. In particular, it also provides an overview of representative natural polysaccharide immunomodulators.

Quercetin is a plant flavonoid with great potential for the prevention and treatment of disease. Despite the curative application of quercetin is hampered by low bioavailability, its core serves as a scaffold for generating more potent compounds with amplified therapeutic window. This review aims to describe recent advances in the improvement of the pharmacokinetic profile of quercetin via the amino acid prodrug approach which offers wide structural diversity, physicochemical and biological properties improvement. According to the findings, conjugation of quercetin with amino acids results in increased solubility, stability, cellular permeability as well as biological activity. In particular quercetin- amino acid conjugates exhibited potent anticancer, MDR-reversal and antibiotic resistance reversal activities. The synthetic pathways and examples of quercetin-amino acid conjugates are considered. Practical considerations and challenges associated with the development of these prodrugs are also discussed. This mini-review covers the literature on quercetin-amino acid conjugates since 2001 when the first thematic work was published.

Natural compounds, such as paclitaxel and camptothecin, have great effects on the treatment of tumors. Such natural chemicals often achieve anti-tumor effects through a variety of mechanisms. Therefore, it is of great significance to conduct further studies on the anticancer mechanism of natural anticancer agents to lay a solid foundation for the development of new drugs. Myricetin, originally isolated from Myrica nagi, is a natural pigment of flavonoids that can inhibit the growth of cancer cells (such as liver cancer, rectal cancer, skin cancer and lung cancer, etc.). It can regulate many intracellular activities (such as anti-inflammatory and blood lipids regulation) and can even be bacteriostatic. The purpose of this paper is to outline the molecular pathways of the anticancer effects of myricetin, including the effect on cancer cell death, proliferation, angiogenesis, metastasis and cell signaling pathway.

Background: Delaying the absorption of glucose through α-glucosidase enzyme inhibition is one of the therapeutic approaches in the management of Type 2 diabetes, which can reduce the incidence of postprandial hyperglycemia. The existence of chronic postprandial hyperglycemia impaired the endogenous antioxidant defense by inducing oxidative stress-induced pancreatic β-cell destruction through uncontrolled generation of free radicals such as ROS, which in turn, leads to various macrovascular and microvascular complications. The currently available α -glucosidase inhibitors, for instance, acarbose, have some side effects such as hypoglycemia at higher doses, liver problems, meteorism, diarrhea, and lactic acidosis. Therefore, there is an urgent need to discover and develop potential α-glucosidase inhibitors. Objective: Based on suchmotifs, researchers are intrigued to search for the best scaffold that displays various biological activities. Among them, coumarin scaffold has attracted great attention. The compound and its derivatives can be isolated from various natural products and/or synthesized for the development of novel α-glucosidase inhibitors. Results: This study focused on coumarin and its derivatives as well as on their application as potent antidiabetic agents and has also concentrated on the structure-activity relationship. Conclusion: This review describes the applications of coumarin-containing derivatives as α - glucosidase inhibitors based on published reports which will be useful for innovative approaches in the search for novel coumarin-based antidiabetic drugs with less toxicity and more potency.

Background: Spirothiazolidines are versatile synthetic scaffold possessing wide spectrum of biological interests involving potential anticancer activity. Objective: To report the first synthesis of Bis Spiro-thiazolidine as a novel heterocyclic ring system. Methods: One-pot three-component reaction including condensation of p-phenyllene diamine; cyclohexanone and thioglycolic acid produced Spiro-thiazolidine 4, which underwent further condensation with cyclohexanone and thioglycolic acid with equimolar ratio to introduce Bis-Spiothiazolidine 5 as the first synthesis. Also, bis spiro-thiazolidine arylidene derivatives 6-13 were synthesized by the reaction of Bis-Spiothiazolidine 5 with different aromatic benzaldehydes. Results: Four compounds 13, 12, 9 and 11 have shown highly significant anticancer activity compared to Doxorubicin® (positive control) against Human liver carcinoma (HepG2) and Human Normal Retina pigmented epithelium (RPE-1) cell lines. Conclusion: The novel bis-spirothiazolidine deriviatives have been synthesized for the first time and showed excellent anticancer activities compare with the corresponding spirothiazolidine derivatives.

Objective: The study aimed to explore the efficacy of pharmacokinetic-based 5-fluorouracil dose management by plasma concentration test in advanced colorectal cancer treatment. Methods: 153 samples of advanced colorectal cancer patients were enrolled and randomly assigned to a control group and an experimental group. All patients received double-week chemotherapy with 5- fluorouracil (four weeks were used as one period), and chemotherapy duration ranged from 2 to 6 periods. In the first period, all patients were administered with the classic strategy of body surface area (BSA). Results: In the subsequent periods, the control group (77 samples) continued with BSA guided chemotherapy, while the experimental group (76 samples) received pharmacokinetic AUC-based chemotherapy. The efficacy and toxic side effects were assessed during chemotherapy, and survival was recorded in a follow-up. In the AUC experimental group, the rate of diarrhea significantly decreased (37.50% vs. 70.00%, P=0.010), and incidence of oral mucositis reduced (54.17% vs. 82.50%, P=0.014). Compared with the control group, the clinical benefit rate of experimental group was much higher (90.79% vs. 79.22%, P=0.046). Conclusion: There was no significant difference in other 5-fluorouracil related toxic side effect events (nausea, vomiting, hand-foot syndrome) and progression-free survival between the two groups. Pharmacokinetic- based dose management of 5-Fluorouracil reduces the toxicity of chemotherapy and improves long-term efficacy of chemotherapy for advanced colorectal cancer patients.