It is difficult to treat malignant tumors, neurodegenerative diseases, and vascular diseases. For pathogenesis complexity of these diseases, researchers have focused on finding more drugs with high efficacy and low side effects. As a potential first-in-class drug, RRx−001 is expected to be an important first-line drug in tumor immunology, radiosensitizer and radio protecter. Currently, RRx−001 entered phase Ⅲ clinical trials. The data of the phase Ⅱ clinical trials demonstrated its safety and effectivity as a single agent and in combination with first-line clinical drugs. The novel mechanisms of RRx−001 and the result of main clinical trials were summarized, which could be valuable to further optimization and clinical application.

Objective To study the antitumor activities of RRx-001 derivatives with novel covalent fragments. Methods Four targeted compounds were designed and synthesized. The structures were confirmed by ¹H NMR and HRMS. A549 and HCT116 cancer cell lines were selected for antiproliferative activity assays. Results All the compounds revealed antitumor activities and compound ZM528 showed the best antitumor activity against these two cell lines with IC₅₀ values of （5.1±4.8） μmol/L and （6.0±2.7） μmol/L, respectively. Conclusion The result indicated that bromoacetyl group of RRx-001 could be substituted with other covalent fragments.

Objective To study anti-inflammatory activities of oridonin derivatives without Michael fragment. Methods Two oridonin sulfonylureas were designed and synthesized by a photocatalysis reaction and a scaffold hopping strategy. The inhibitory rate of IL-1β was selected for anti-inflammatory activity evaluation. Results Both compound ZM658 and ZM659 revealed potent anti-inflammatory activities with the values of 69.3% and 59.7% in THP-1 cells, respectively. Moreover, two compounds also showed dose-dependent and low cytotoxicity. Conclusion The result indicated that Michael receptor fragment of oridonin could be substituted with sulfonylurea group.

Allergic rhinitis (AR), a globally prevalent immune-mediated inflammatory condition, is still an incurable disease. In the present study, we have validated the impact of the Kelch-like ECH associated protein 1 (Keap1)-related oxidative stress and inflammatory response in clinical AR patient peripheral blood and nasal swab samples, emphasizing the biological relevance of Keap1 and AR. Targeting Keap1 -nuclear factor erythroid 2-related factor 2 (Nrf2) related anti-oxidative stress may be effective for AR intervention. Drawing inspiration from the Keap1 homodimerization and the E3 ligase characteristics, we herein present a design of novel bivalent molecules for chemical knockdown of Keap1. For the first time, we characterized ternary complexes of Keap1 dimer and one molecule of bivalent compounds. The best bivalent molecule 8 encompasses robust capacity to degrade Keap1 as a homoPROTAC^KEAP1. It efficaciously suppresses inflammatory cytokines in extensively different cells, including human nasal epithelial cells. Moreover, in an AR mouse model, we confirmed that the chemical degradation induced by homoPROTAC^KEAP1 led to therapeutic benefits in managing AR symptoms, oxidative stress and inflammation. In summary, our findings underscore the efficacy of targeting the Keap1 system through the homoPROTAC-ing technology as an innovative and promising treatment strategy for the incurable allergic disorders.

Objective To find novel lead compounds as p53-MDM2 inhibitors by drug repurposing strategy. Methods The p53-MDM2 inhibitory activities of compounds were determined by FP and western blotting. MTT method was used to determine the in-vitro antitumor activities. The metabolites in human liver microsomes were tested. Results Bepridil showed excellent in-vitro anti-tumor activity and strong p53-MDM2 protein binding inhibitory activity, which can significantly reduce the expression of MDM2 protein in a dose-dependent manner. The metabolites in human liver microsomes are mainly benzene ring hydroxyl mono-oxidation metabolites. Conclusion Bepridil can be used as a lead compound for p53-MDM2 protein binding small molecule inhibitors for subsequent structural optimization design studies.

Objective To search for novel potent 3-ester derivatives of arenobufagin and test their antitumor activities in vitro. Methods Target compounds were synthesized by esterification of arenobufagin with acids. CellTiter method was used to assay the in vitro antitumor activities. Results 3-Ester derivatives exhibited excellent antitumor activities against all the cancer cells. Conclusion Among the 3-ester derivatives, compound 2a had the best activities with the IC₅₀ of 4.0−91.7 nmol/L and appeared to be a valuable candidate for further study.

Objective To develop novel NAE inhibitors with non-nucleoside scaffold by a scaffold hopping strategy and study the in vitro antitumor activities. Methods Disulfonamideindazole 14 was synthesized through 23 steps with a good yield. Its chemical structure was confirmed by ¹H NMR and MS. MTT method was used to determine the in vitro antitumor activities. Results Compound 14 exhibited moderate antitumor activities against various cancer cells and promoted significant UBC12 accumulation in a dose-dependent manner. Conclusion Compound 14 is a potent NAE inhibitor with remarkable apoptosis induction and cell cycle arrest in prostate cancer PANC-1 cells. Our work provides a valuable leading compound for the further design and development of NAE inhibitors.

Objective To investigate the incidence of left ventricular hypertrophy (LVH) in peritoneal dialysis (PD) patients with different hydration statuses,and analyze the risk factors of LVH in PD patients.Methods PD patients in Renji Hospital,Shanghai Jiao Tong University School of Medicine from September 2016 to January 2017 were enrolled.Demographic data of patients were collected and biochemical parameters were measured.Hydration status index overhydration (OH) was measured by bioimpedance spectroscopy,and LVH was diagnosed by echocardiography.Logistic regression was used to analyze the risk factors of LVH.Results A total of 113 PD patients aged 58.98(48.89,65.33) years with median PD duration 46.20(18.08,72.75) months were enrolled in present study,among whom 60 patients (53.1％) had LVH.OH ＞ 1.1 L was detected in 80 patients (70.8％),among whom 34 patients (42.5％) had subclinical overhydration (SCOH).LVH was however diagnosed in 33(71.7％) clinical overhydrated (COH) patients and 17(50.0％) SCOH patients (n=34).In the normal hydrated (OH≤1.1 L) patients (n=33),LVH was detected in 10 patients (30.3％).Multivariate logistic regression showed that high OH (OR=1.730,95％CI 1.274-2.348,P ＜ 0.001) and low hemoglobin (OR=0.965,95％CI 0.940-0.991,P=0.008) were the independent risk factors of LVH.Conclusions LVH is common in PD patients,especially in overhydrated patients.High OH and low hemoglobin were the independent risk factors of LVH.

Objective To study the hemostasis activity of iodine complex with carboxymethyl chitosan .Methods The polymers were prepared with azodiisobutyronitrile as the initiating agent and sodium acrylate ,N‐vinylpyrrolidone ,carboxym‐ethyl chitosan and N ,N′‐methylene diacrylamide as the raw materials .It was then complexed with iodine to generate iodine complex with carboxymethyl chitosan ,and the hemostasis activity was tested at the same time .Results The polymers could absorb water with the value of 103g/g and showed potent hemostasis activity for auricular veins and femoral veins .Conclusion The results showed that hemostatic effect of polymers was better than that of hemostatic sponge and Quikclot .