4,6-Disubstituted-1H-Indazole-4-Amine derivatives with immune-chemotherapy effect and in vivo antitumor activity.

Tryptophan-2,3-dioxygenase (TDO) and indoleamine-2, 3-dioxygenase 1 (IDO1) are the important tumor immune checkpoints and TDO and IDO1 inhibition may present a potential approach to activate the T cell-mediated antitumor immune response during cancer treatment. Herein, we designed and synthesized a series of nitro-aryl 1H-indazole derivatives. SARs analysis showed that the nitro-aryl at the C-4 position of 1H-indazole was beneficial for TDO inhibition and directly tumoricidal effect and the substituents at C-6 position of 1H-indazole significantly affected the activity and selectivity of IDO1/TDO. Among these derivatives, HT-28 and HT-30 demonstrated nanomolar potency and excellent selectivity against TDO with IC50 values of 0.62 µM and 0.17 µM respectively, and HT-37 showed the IDO1 and TDO dual-target inhibitory activity with IC50 values of 0.91 µM and 0.46 µM against IDO1 and TDO. Moreover, HT-28 showed the significant tumoricidal effect on six tumor cell lines, while HT-30 and HT-37 had almost no cytotoxic activity on these tumor cells. In the CT-26 allograft BALB/c mice, HT-28 had the significant in vivo antitumor activity at a lower dose. IHC staining assay indicated that HT-28 could reduce the expression of Foxp3 and enhance the expression of CD8 and TNF-α in tumor tissue. In summary, we developed a difunctional monomer with immune-chemotherapy effect to obtain the better in anti-tumor activity.

Current Research on Pro-drug Therapies for Parkinson's and Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) and Parkinson's (PD) disease are common neurodegenerative conditions of the Central Nervous System (CNS). Thus, these diseases have only been treated symptomatically since no approved drug is available that provides a complete cure. OBJECTIVES: Through reading relevant literatures published at home and abroad, the method and significance of prodrug strategy to increase the efficacy of ad and pd drugs were discussed. METHODS: The biological mechanisms and currently approved drugs for both diseases have been discussed, revealing that most of these treatments utilized existing prodrug design strategies, including increased lipophilicity, and the use of transporters mediation and bio-oxidation to improve oral bioavailability and brain permeability. RESULTS: The purpose of this paper is to review the research progress in the treatment of Neurodegenerative Diseases (NDDS), especially ad and pd, using the prodrug strategy. The research of drug bioavailability and the prodrug strategy of cns targeted drug delivery lay the foundation for drug development to treat these diseases. CONCLUSION: The use of prodrug strategies provides important opportunities for the development of novel therapies for ad and pd.

X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson's Disease.

Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson's disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to 23, which manifested IC50 values of 0.64 and 0.04 µM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. 23 showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, 23 likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.

Pioglitazone Metformin Complex Improves Polycystic Ovary Syndrome Comorbid Psychological Distress via Inhibiting NLRP3 Inflammasome Activation: A Prospective Clinical Study.

OBJECTIVE: This study aimed at investigating the therapeutic effect and mechanism of pioglitazone metformin complex preparation (PM) in polycystic ovary syndrome (PCOS) comorbid psychological distress. METHODS: Seventy-five patients with PCOS comorbid psychological distress were randomly allocated into the PM, metformin, and placebo groups. The primary efficacy measure was the change from baseline to week 12 on the Symptom Checklist 90-R (SCL-90-R) scores. NLRP3 inflammasome, IL-1ß, IL-6, TNF-α, and biochemical parameters were determined at baseline and at week 12. The participants were required to meet the criteria for PCOS (Rotterdam, NIH) and psychological distress (any factor scores of SCL - 90 - R > 2). RESULTS: The participants had significantly high scores on the SCL-90-R scales of anxiety and depression. PM significantly decreased anxiety and depression symptom severity (from 2.31 ± 0.75 to 1.65 ± 0.38, p < 0.001, and from 2.08 ± 0.74 to 1.61 ± 0.46, p = 0.010, at week 12, respectively). PM significantly decreased the expression of NRPL3 and caspase-1. Patients in the PM group experienced a significant reduction in IL-1ß (from 98.42 ± 14.38 to 71.76 ± 13.66, p = 0.02), IL-6 (from 87.51 ± 8.74 to 71.98 ± 15.87, p = 0.02), and TNF-α (from 395.33 ± 88.55 to 281.98 ± 85.69, p = 0.04). PM was superior to metformin in reducing total testosterone (2.24 ± 0.74 versus 3.06 ± 0.83, p = 0.024, at week 12). CONCLUSIONS: This study is the first to reveal that PM alleviates psychological distress via inhibiting NLRP3 inflammasome and improves several markers, including total testosterone.

[Clinical study on adverse reactions of peginterferon alfa-2a in treatment of chronic hepatitis in adults and children].

OBJECTIVE: To investigate the scope and degree of short-term adverse reactions of peginterferon alfa-2a in treatment of chronic hepatitis in adults and children to provide basis for anti-viral treatment in clinical practice. METHODS: A prospective study was conducted in adults and children with chronic hepatitis treated with peginterferon alfa-2a. Meanwhile, the reactions in the patients were recorded with a table designed by ourselves and statistically analyzed. RESULTS: The short-term adverse reactions included increase in body temperature and aching pain in joints and muscles. The increase in body temperature was the major reaction and accounted for 54.11%. The increase in body temperature began to appear in 47.6% of the patients. The body temperature was 37.3 degrees C-38.9 degrees C in most of the patients and mediate and low increase was found in 85.4% of the patients, which was decreased to 70% in the 4th week. However, the percentage of patients with high temperature was increased from 14.5% in the 1st week to 30% in the 4th week. The increase of body temperature began to appear in 9-12 h and 3-5 h after injection of peginterferon alfa-2a in the 1st and later, respectively. The duration of fever was 3-4 h in most of the patients. It appeared once in 1 week after the rejection in most of the patients. For management of fever, cooling with medication was conducted in 45.5 % of the patients. CONCLUSION: The short-term adverse reactions in patients with chronic hepatitis treated with peginterferon alfa-2a include the increase in body temperature etc. The severity of the adverse reactions gradually reduces with continuation of the treatment. Of the adverse reactions, the increase in body temperature is the major (47.6%) and others only account for 1%-16.9%. The increase in body temperature is mainly transient and no management is needed in 50% of the patients. Since the "ladder-type" dose-adding method is used for administration of peginterferon alfa-2a in this group of patients, the adverse reactions are low in number and mild in degree.