Synthesis of Novel Fluorinated Xanthine Derivatives with High Adenosine A2B Receptor Binding Affinity

The G protein-coupled adenosine A2B receptor is suggested to be involved in various pathological processes accompanied by increased levels of adenosine as found in inflammation, hypoxia, and cancer. Therefore, the adenosine A2B receptor is currently in focus as a novel target for cancer therapy as well as for noninvasive molecular imaging via positron emission tomography (PET). Aiming at the development of a radiotracer labeled with the PET radionuclide fluorine-18 for imaging the adenosine A2B receptor in brain tumors, one of the most potent and selective antagonists, the xanthine derivative PSB-603, was selected as a lead compound. As initial biodistribution studies in mice revealed a negligible brain uptake of [3H]PSB-603 (SUV3min: 0.2), structural modifications were performed to optimize the physicochemical properties regarding blood–brain barrier penetration. Two novel fluorinated derivatives bearing a 2-fluoropyridine (5) moiety and a 4-fluoro-piperidine (6) moiety were synthesized, and their affinity towards the four adenosine receptor subtypes was determined in competition binding assays. Both compounds showed high affinity towards the adenosine A2B receptor (Ki (5) = 9.97 ± 0.86 nM; Ki (6) = 12.3 ± 3.6 nM) with moderate selectivity versus the other adenosine receptor subtypes.

Development and Validation of UV-Spectrophotometric Method for Estimation of Doxofylline in Bulk and Tablets

Doxofylline is a xanthine derivative and it has its application as a bronchodilator in different pulmonary conditions like asthma and COPD (chronic obstructive pulmonary disease). The research was conducted with the objective to develop and validate a simple, easy, rapid and cost-effective UV-Spectrophotometric method to estimate the amount of doxofylline in bulk and tablets. The validating parameters and methodology were selected and performed according to ICH and USP guidelines. In the accuracy study, the mean % recovery was within the limit (100.20%) with %RSD 0.77. The mean of % assay and %RSD of intra-assay precision study was found 99.81 and 0.79 respectively with only 0.57% variation between two analysts in intermediate precision study. The linearity study demonstrated the value of the correlation coefficient is 0.9999 whereas the robustness studies showed a slight but negligible variation of absorbance while changing different operating parameters. In system suitability study, the %RSD was found less than 2.00%. According to the specificity study, there were no placebo and diluent effect on the absorbance measurements.

The protective effect of Pentoxifylline on testopathy in male rats following Dimethyl Nitrosamine administration: An experimental study

Background: Nitrosamines as a carcinogenic agent has unfavorable effects on some of the male reproductive parameters. Pentoxifylline (PX) is a xanthine derivative used as a drug inhibiting the inflammatory factors, reducing blood viscosity, improving peripheral blood flow, and so on. Objective: The aim of the present study is to evaluate the effects of PX against Dimethyl nitrosamine (DMN)-inducing the damage to the reproductive parameter of male rats. Materials and Methods: In this experimental study, 48 male Wistar rats (8 wk, 220- 250 gr) were randomly assigned to eight groups (n = 6/each): normal control and DMN control groups (40 mg/kg); PX groups (25, 50, 100 mg/kg), and DMN + PX groups (25, 50, 100 mg/kg). Treatments were administered intraperitoneally and the gavage applied daily for 28 days. The sperm parameters, spermatogenesis index, total antioxidant capacity, testosterone level, and seminiferous tube diameter were assessed. Results: The values of all parameters reduced significantly in the DMN control group compared to the normal control group (p < 0.001). The PX and PX + DMN treatments at all entirely doses improved all parameters significantly compared to the DMN control group (p < 0.001). Conclusion: DMN caused detrimental effects on reproductive parameters. Also, no significant modifications were observed in PX treatments at all doses compared to the normal control group. PX compensated the toxic effect of DMN on reproductive parameters. Key words: Dimethyl nitrosamine, Reproductive, Pentoxifylline, Rat.

1,3,7,8-SUBSTITUTED XANTHINE DERIVATIVES AS POTENTIAL ANTIASTHMATIC AGENTS WHICH ACT ON ADENOSINE RECEPTOR

Asthma is one of the most common chronic diseases in modern society. There is a high prevalence of usage of complementary medicine for asthma. Xanthine derivatives which act on adenosine receptor have been cited as a most popular complementary treatment. This studys was undertaken to determine if there is any evidence for the clinical efficacy of xanthine derivatives for the treatment of asthma symptoms. This review highlights the more recent developments in the design and optimization of xanthine derivatives which act on A2A and A2B adenosine receptor. 1,3,8 and 1,3,7,8-substituted xanthine derivatives were found to be effetive. 1,3,7,8 Substituted xanthine derivative possess good affinity on A2A and A2B AR and are not selective for one particular receptor. This is benefitical for decreasing the side effects related to CVS.

Propentofylline decreases hypothalamic astrogliosis induced by hypercaloric diet in the rat

ABSTRACT Obesity is associated with a chronic and low-grade inflammatory response in the hypothalamus, where astrogliosis occurs with the upregulation of the astrocyte structural protein GFAP. As propentofylline (PPF) has inhibitory effects on astrocyte and microglial activation during inflammation, this study aimed to investigate if this xanthine derivative could decrease the astrocyte reaction induced by a hypercaloric diet (HD). Male Wistar rats were divided into four groups: NDS – rats receiving a normocaloric diet (ND) and daily saline solution; NDP – rats receiving ND and daily PPF (12.5 mg/kg/day, intraperitoneal route); HDS – rats receiving HD and saline solution, HDP – rats receiving HD and PPF. On the 21st day, rats were anesthetized, and perfused, and brains were collected for GFAP immunohistochemical study in the hypothalamus. Results showed that HD induced increased weight gain and hypothalamic astrogliosis. Propentofylline decreased the expression of GFAP in the HDP group, although it did not affect the weight gain induced by this diet.

Propentofylline reduces glial scar development following gliotoxic damage in the rat brainstem

ABSTRACT Propentofylline is a xanthine derivative that depresses activation of glial cells, whose responses contribute to neural tissue damage during inflammation. Ethidium bromide injection into the central nervous system induces local oligodendroglial and astrocytic loss, resulting in primary demyelination, neuroinflammation and blood-brain barrier disruption. Surviving astrocytes present a vigorous reaction around the injury site with increased immunoreactivity to glial fibrillary acidic protein (GFAP). Objective This study aimed to evaluate the effect of propentofylline administration on astrocytic response following gliotoxic injury. Method Wistar rats were injected with ethidium bromide into the cisterna pontis and treated or not with propentofylline (12.5mg/kg/day, intraperitoneal) during the experimental period. Brainstem sections were collected from 15 to 31 days after gliotoxic injection and processed for GFAP immunohistochemistry. Results and Conclusion Results demonstrate that propentofylline decreased astrocytic activation until the 21st day, suggesting that this drug may have a role in reducing glial scar development following injury.