Primary neuroendocrine carcinoma of cervical lymph node masquerading as non-Hodgkin lymphoma: A diagnostic challenge.

ABSTRACT: A large extended family of tumors classified as neuroendocrine tumors most commonly occurs in the gastrointestinal tract and bronchus pulmonary tree. It is extremely unusual for a primary neuroendocrine tumor to present as a cervical lymph node mass at initial presentation. We discuss the rare case of a 55-year-old man who initially complained of a right neck mass that was misinterpreted as non-Hodgkin lymphoma on fine needle aspiration cytology. By integrating clinical findings, radiography, fine-needle aspiration cytology, histomorphology, and immunohistochemistry analysis, a definitive diagnosis of primary neuroendocrine carcinoma of the cervical lymph node was made. He received chemotherapy and decompressive radiation as treatment. Regarding the course of disease in the present case, the patients underwent a distant subcutaneous metastasis over the right anterior chest wall 10 months after the initial manifestation. The patient is still alive, albeit his general condition has gotten deteriorated, and he is getting regular follow-ups.

Mitigating neuroinflammation in Parkinson's disease: Exploring the role of proinflammatory cytokines and the potential of phytochemicals as natural therapeutics.

Parkinson's disease (PD) is one of the most prevalent neuroinflammatory illnesses, characterized by the progressive loss of neurons in the brain. Proinflammatory cytokines play a key role in initiating and perpetuating neuroinflammation, which can lead to the activation of glial cells and the deregulation of inflammatory pathways, ultimately leading to permanent brain damage. Currently, available drugs for PD mostly alleviate symptoms but do not target underlying inflammatory processes. There is a growing interest in exploring the potential of phytochemicals to mitigate neuroinflammation. Phytochemicals such as resveratrol, apigenin, catechin, anthocyanins, amentoflavone, quercetin, berberine, and genistein have been studied for their ability to scavenge free radicals and reduce proinflammatory cytokine levels in the brain. These plant-derived compounds offer a natural and potentially safe alternative to conventional drugs for managing neuroinflammation in PD and other neurodegenerative diseases. However, further research is necessary to elucidate their underlying mechanisms of action and clinical effectiveness. So, this review delves into the pathophysiology of PD and its intricate relationship with proinflammatory cytokines, and explores how their insidious contributions fuel the disease's initiation and progression via cytokine-dependent signaling pathways. Additionally, we tried to give an account of PD management using existing drugs along with their limitations. Furthermore, our aim is to provide a thorough overview of the diverse groups of phytochemicals, their plentiful sources, and the current understanding of their anti-neuroinflammatory properties. Through this exploration, we posit the innovative idea that consuming nutrient-rich phytochemicals could be an effective approach to preventing and treating PD.

Solitary superficial angiomyxoma of the ear pinna: a diagnostic dilemma with a review of literature.

Superficial angiomyxoma is an extremely rare subcutaneously placed myxoid soft tissue neoplasm. There are few case reports with fine needle aspiration cytological and histopathological findings available for this tumor because of its rarity. Here, we describe a case of superficial angiomyxoma in a 24-year-old girl who had a solitary left ear pinna mass without a Carney's complex at the time of presentation or at the end of two years of follow-up next to the surgical removal of the tumor. The clinical, cytomorphological, and histological findings, together with the immunohistochemical markers, in a case of superficial angiomyxoma are described in this rare case report for the first time in the English literature.

Primary Cardiac Sarcoma: Clinical Characteristics and Prognostic Factors over the Past 2 Decades.

BACKGROUND: Primary cardiac sarcomas (PCS) are extremely rare malignant tumors involving the heart. Only isolated case reports have been described in the literature over different periods of time. This pathology has been associated with a dismal prognosis and given its rarity; treatment options are very limited. Furthermore, there are contrasting data about the effectiveness of current treatment modalities in improving the survival of patients with PCS, including surgical resection which is the mainstay of therapy. There is a paucity of data on the epidemiological characteristics of PCS. This study has the objective of investigating the epidemiologic characteristics, survival outcomes, and independent prognostic factors of PCS. METHODS: A total of 362 patients were ultimately registered in our study from the Surveillance, Epidemiology, and End Results (SEER) database. The study period was from 2000 to 2017. Demographics such as clinical characteristics, overall mortality (OM), and PCS-specific mortality (CSM) were taken into account. A p value of <0.1 in the univariate analysis leads to the incorporation of the variable into multivariate analysis adjusting for covariates. Adverse prognostic factors were represented by a Hazard Ratio (HR) greater than one. The five-year survival analysis was carried out using the Kaplan-Meier method and the log-rank test was used to compare survival curves. RESULTS: Crude analysis revealed a high OM in age 80+ (HR = 5.958, 95% CI 3.357-10.575, p < 0.001), followed by age 60-79 (HR = 1.429, 95% CI 1.028-1.986, p = 0.033); and PCS with distant metastases (HR = 1.888, 95% CI 1.389-2.566, p < 0.001). Patients that underwent surgical resection of the primary tumor and patients with malignant fibrous histiocytomas (HR = 0.657, 95% CI 0.455-0.95, p = 0.025) had a better OM (HR = 0.606, 95% CI 0.465-0.791, p < 0.001). The highest cancer-specific mortality was observed in age 80+ (HR = 5.037, 95% CI 2.606-9.736, p < 0.001) and patients with distant metastases (HR = 1.953, 95% CI 1.396-2.733, p < 0.001). Patients with malignant fibrous histiocytomas (HR = 0.572, 95% CI 0.378-0.865, p = 0.008) and those who underwent surgery (HR = 0.581, 95% CI 0.436-0.774, p < 0.001) had a lower CSM. Patients in the age range 80+ (HR = 13.261, 95% CI 5.839-30.119, p < 0.001) and advanced disease with distant metastases (HR = 2.013, 95% CI 1.355-2.99, p = 0.001) were found to have a higher OM in the multivariate analyses adjusting for covariates). Lower OM was found in patients with rhabdomyosarcoma (HR = 0.364, 95% CI 0.154-0.86, p = 0.021) and widowed patients (HR = 0.506, 95% CI 0.263-0.977, p = 0.042). Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality of the same groups, and lower mortality in patients with Rhabdomyosarcoma. CONCLUSION: In this United States population-based retrospective cohort study using the SEER database, we found that cardiac rhabdomyosarcoma was associated with the lowest CSM and OM. Furthermore, as expected, age and advanced disease at diagnosis were independent factors predicting poor prognosis. Surgical resection of the primary tumor showed lower CSM and OM in the crude analysis but when adjusted for covariates in the multivariate analysis, it did not significantly impact the overall mortality or the cancer-specific mortality. These findings allow for treating clinicians to recognize patients that should be referred to palliative/hospice care at the time of diagnosis and avoid any surgical interventions as they did not show any differences in mortality. Surgical resection, adjuvant chemotherapy, and/or radiation in patients with poor prognoses should be reserved as palliative measures rather than an attempt to cure the disease.

Site-Selective Synthesis of C-17 Ester Derivatives of Natural Andrographolide for Evaluation as a Potential Anticancer Agent.

A library of 57 compounds of natural andrographolide was designed, synthesized, and screened for in vitro studies against four human cancer cell lines: A594, PC-3, MCF-7, and HCT-116. Most of the synthesized compounds displayed better cytotoxic profile against all tested cells compared to the parent andrographolide (1). The tested semisynthetic derivatives of andrographolide were found to be more sensitive toward lung carcinoma (A594) and prostate carcinoma (PC-3) cell lines. Among the synthesized compounds, the C-17 p-methoxy phenyl ester analog 8s inhibited cell proliferation effectively in A549 (IC50: 6.6 µM) and PC-3 (IC50: 5.9 µM) cell variants, and compound 9s exhibited the most potent activity against the A594 cell line, with an IC50 value of 3.5 µM. Further anticancer mechanistic investigation demonstrated that compound 9s displayed nuclear morphological changes and increased reactive oxygen species (ROS) with disturbed mitochondrial membrane potential (MMP) that can lead to apoptosis. To know the exact structure confirmation of intermediate compounds 4 and 5, single X-ray crystallography was performed, which supported the complete reaction design of this work.

Gain of function studies on predicted host receptors for white spot virus.

Three decades after its first outbreak, the shrimp white spot virus (WSV) is still a global cause of concern due to considerable losses and lack of effective control measures. Several candidate host receptor proteins have been identified, but the pathogenesis is not clearly understood, although the key role of the WSV envelope protein VP28 in virus internalization is established. Here, protein-protein docking is applied to evaluate the interaction of VP28 trimeric extracellular region with four host (Penaeus monodon) receptors reported earlier, Rab7 GTPase (PmRab7), glucose transporter 1 (PmGLUT1), C-type lectin (PmCTL) and calreticulin (PmCRT). The stability of predicted complexes evaluated in terms of binding energy per unit buried surface area ranged from -8.46 to -11.82 cal mol-1/Å2, which is not sufficient for functional interaction. Nevertheless, each of these host proteins was tested by a gain-of-function approach by observing their ability to make a fish cell line permissive to the shrimp WSV. Full-length expression constructs of the four receptors were transfected into SSN1 snakehead fish cells that are non-permissive to WSV. Transfected SSN1 cells and WSV permissive insect Sf9 cells were challenged with purified WSV. After 24 h, the presence of receptor transcripts was confirmed in the treated SSN1 cells, and not in the non-transfected SSN1 cells. Further, vp28 transcript was detected in Sf9 cells, but not in any of the treated SSN1 cells, indicating that none of the receptors were singly sufficient to make SSN1 cells permissive to WSV, even though PmRab7 was a strong candidate that alone showed >85% protection in virus neutralization experiments. For the other 3 candidates, previous reports predicted the involvement of co-receptors, which is confirmed here by their inability to act singly.

Synthesis of 3-N-/O-/S-methyl-imidazo[1,2-a] pyridine derivatives for caspase-3 mediated apoptosis induced anticancer activity.

A library of 49 analogs of imidazo[1,2-a]pyridine with 2-halo, aryl, styryl and phenylethynyl-substitution at C-2 position and N-/O-/S-methyl linkage at C-3 position, have been synthesized and evaluated for their anti-proliferative activity against breast (MCF-7, MDA-MB-231), pancreatic (MiaPaca-2), lung (A549), prostate (PC-3) and colon (HCT-116) cancer cell lines and normal cells (HEK-293). Among the screened compounds, 5b exhibited best anticancer potential in all tested cancer cells with IC50 ranging from 3.5 to 61.1 µM and no toxicity in normal cells. Further, mechanistic study of 5b revealed concentration dependent increased generation of ROS, reduced mitochondrial membrane potential (MMP), surface and nuclear morphological alterations and inhibition of colony formation in HCT-116 cells. Western blot results had shown that the cell death in HCT-116 colon cancer cells was achieved through the induction of apoptosis via upregulation of the PTEN gene and downregulation of AKT pathway. Similarly, 5b treatment induced caspase-3 cleavage which is a hallmark of apoptosis. Molecular docking and binding energy (ΔG) studies of hit 5b with respect to three important cancer targets (EGFR, mTOR and PI3Kα) revealed strong binding of inhibitor with PI3Kα (docking score -6.932 and ΔG -56.297).

Organocatalyzed umpolung addition for synthesis of heterocyclic-fused arylidene-imidazolones as anticancer agents.

A strategy of "Nature-to-new" with iterative scaffold-hopping was considered for investigation of privileged ring/functional motif-elaborated analogs of natural aurones. An organocatalyzed umpolung chemistry based method was established for molecular-diversity feasible synthesis of title class of chemotypes i.e. (Z)-2-Arylideneimidazo[1,2-a]pyridinones and (Z)-2-Arylidenebenzo[d]imidazo[2,1-b]thiazol-3-ones. Various biophysical experiments indicated their important biological properties. The analogs showed characteristic anticancer activities with efficiency more than an anticancer drug. The compounds induced apoptosis with arrest in the S phase of the cell cycle regulation. The compounds' significant effect in up/down-regulation of various apoptotic proteins, an apoptosis cascade, and the inhibition of topoisomerases-mediated DNA relaxation process was identified. The analysis of the structure-activity relationship, interference with biological events and the drug-likeness physicochemical properties of the compounds in the acceptable window indicated distinctive medicinal molecule-to-properties of the investigated chemotypes.

Exploration of Benzo[b]carbazole-6,11-diones as anticancer agents: Synthesis and studies of hTopoIIα inhibition and apoptotic effects.

Two series of (hetero)arylamino-naphthoquinones and benzo-fused carbazolequinones were considered for study with the rationale that related structural motifs are present in numerous drugs, clinical trial agents, natural products and hTopoIIα inhibitors. Total 42 compounds were synthesized by reactions including dehydrogenative CN and Pd-catalyzed CC bond forming transformations. These compounds were screened against numerous cancer cells including highly metastatic one (MCF-7, MDA-MB-231, H-357 and HEK293T), and normal cells (MCF 10A). Some of the active compounds were evaluated for clonogenic cell survival and apoptotic effects in cancer cells (DAPI nuclear staining, Comet assay, Annexin-V-FITC/PI dual staining, flow cytometry, and western blot analysis with relevant proteins). All compounds were tested for hTopoIIα inhibitory activity. The investigated series compounds showed important properties like significant apoptotic antiproliferation in cancer cells with cell cycle arrest at S-phase and downregulation of NF- κß signaling cascade, relatively less cytotoxicity to normal cells, and hTopoIIα inhibition with more efficiency compared to an anticancer drug etoposide.

Effects of Injectable Trace Minerals (ITMs) on Th1/Th2 Cytokine Balance of Newborn Calves with Tropical Theileriosis.

Injectable trace minerals (ITMs) could provide a potential alternative way of trace mineral delivery for sick animals. Therefore, evaluation of ameliorative potentials of ITMs (copper, manganese, selenium, and zinc) on the circulating Th1/Th2 cytokine misbalance in Theileria annulata-infected calves was aimed. Forty-three T. annulata-infected newborn calves were randomly allocated into four groups: buparvaquone alone-treated group (BUPA), buparvaquone + oxytetracycline (BUPA + OXY)-treated group, buparvaquone + injectable trace minerals (BUPA + ITMs)-treated group, and BUPA + OXY + ITM-treated group. Blood samples were collected from each of the calves before the start of therapy (day 0) and on day 14 post-therapy. Serum contents of pro- and anti-inflammatory cytokines were estimated by bovine specific ELISA kits. On day 14 post-therapy, significant amelioration in the circulating levels of the studied cytokines was not observed in the calves treated with BUPA, while the calves treated with BUPA + OXY revealed significant (P ≤ 0.04) amelioration in the circulating tumour necrosis factor-α (TNF-α) level. The calves treated with BUPA + ITMs revealed significant (P ≤ 0.041) elevation in the circulating interferon-γ (IFN-γ) and significant (P ≤ 0.011) reduction in the interleukin-10 (IL-10) levels. Moreover, the calves treated with BUPA + OXY + ITMs revealed significant reduction in TNF-α (P ≤ 0.0001) and IL-10 (P ≤ 0.012) contents, and significant elevation in IFN-γ (P ≤ 0.0002) content on day 14 post-therapy. None of the treated calve group revealed significant alteration in the circulating level of transforming growth factor-ß (TGF-ß) on day 14 post-therapy. In conclusion, administration of ITMs to the therapeutic regimen of newborn calves with tropical theileriosis could be a promising therapeutic strategy. ITMs can be recommended for the amelioration of immunological misbalance due to tropical theileriosis in newborn calves.

Development of cost effective metal oxide semiconductor based gas sensor over flexible chitosan/PVP blended polymeric substrate.

In the present work, biodegradable and flexible chitosan/polyvinylpyrrolidone (CHP) polymeric substrate was fabricated by solvent casting method. This is a novel demonstration of the combination of natural polymer (chitosan) and synthetic polymer (PVP) for next-generation semiconductor device applications. The ZnO thin films were successfully synthesized on these polymeric substrates by facile drop-casting method for gas sensing applications. The hydrogen gas sensing properties of ZnO deposited on the polymeric substrate and SiO2 substrate show similar performance. The structural, morphological, optical, thermal, and tensile strength of the CHP substrate were studied using X-ray diffraction (XRD), Scanning electron microscopy (SEM), UV-visible spectroscopy, Derivative thermogravimetric analysis (DTG), and Universal testing machine (UTM), respectively. Our study suggests that the biodegradable CH/PVP flexible polymeric substrate provides a new way for the implementation of an eco-friendly green substrate in numerous electronic device applications.

Andrographolide: Chemical modification and its effect on biological activities.

The major natural bioactive constituent of Andrographis paniculata (AP) (Burm. f.) Nees Andrographolide (1) and its derivatives are well acknowledged in literature for its biological activities such as anti-cancer, anti-diabetic, anti-inflammatory, anti-bacterial, anti-malarial, antihepatitis, anti-HIV, anti-atherosclerosis, hepatoprotective, FXR antagonist, and α-glucosidase inhibition. Many reports are available related to Andrographolide (1) but a consolidated review on the chemical modification of andrographolide with special emphasis on its different functional groups with respect to their biological activities is still missing from the previous literature. Therefore, herein we have collected a literature for the period 2009 onwards in relation to chemistry on andrographolide (1) and its effect on respective biological activity. Also, special attempt on increasing the bioavailability of andrographolide (1) has been given for the designing of various targeted drug delivery systems.

Genome-Wide Analysis and Expression Profiling of Rice Hybrid Proline-Rich Proteins in Response to Biotic and Abiotic Stresses, and Hormone Treatment.

Hybrid proline-rich proteins (HyPRPs) belong to the family of 8-cysteine motif (8CM) containing proteins that play important roles in plant development processes, and tolerance to biotic and abiotic stresses. To gain insight into the rice HyPRPs, we performed a systematic genome-wide analysis and identified 45 OsHyPRP genes encoding 46 OsHyPRP proteins. The phylogenetic relationships of OsHyPRP proteins with monocots (maize, sorghum, and Brachypodium) and a dicot (Arabidopsis) showed clustering of the majority of OsHyPRPs along with those from other monocots, which suggests lineage-specific evolution of monocots HyPRPs. Based on our previous RNA-Seq study, we selected differentially expressed OsHyPRPs genes and used quantitative real-time-PCR (qRT-PCR) to measure their transcriptional responses to biotic (Magnaporthe oryzae) and abiotic (heat, cold, and salt) stresses and hormone treatment (Abscisic acid; ABA, Methyl-Jasmonate; MeJA, and Salicylic acid; SA) in rice blast susceptible Pusa Basmati-1 (PB1) and blast-resistant near-isogenic line PB1+Pi9. The induction of OsHyPRP16 expression in response to the majority of stresses and hormonal treatments was highly correlated with the number of cis-regulatory elements present in its promoter region. In silico docking analysis of OsHyPRP16 showed its interaction with sterols of fungal/protozoan origin. The characterization of the OsHyPRP gene family enables us to recognize the plausible role of OsHyPRP16 in stress tolerance.

Carbon-sulphur cross coupling reactions catalyzed by nickel-based coordination polymers based on metalloligands.

This work illustrates two Ni2+ based coordination polymers (CPs, 1-Ni and 2-Ni) synthesized using two related Co3+ based metalloligands offering appended arylcarboxylate groups. The crystal structure of 1-Ni displays a porous 3D network having well-defined major and minor pores whereas 2-Ni exhibits a somewhat densely packed structure. Both CPs supported the exchange of coordinated water molecules and the inclusion of iodine within their porous structure whereas binding studies illustrated that the Ni(ii) ion in these CPs can bind thiophenol, a reagent used in the C-S cross coupling reactions. The two CPs functioned as the reusable heterogeneous catalysts for the C-S cross coupling reactions between substituted aromatic halides and thiophenol as well as cyclohexanethiol and ethanethiol.

Synthesis and Evaluation of a New Series of 8-(2-Nitroaryl)Xanthines as Adenosine Receptor Ligands.

Preclinical Research A new series of 1,3-dimethylxanthine derivatives bearing 8-(2-nitroaryl) residue was synthesized and evaluated for affinity for recombinant human adenosine receptors subtypes. Nitrate esters of 7-substituted-1,3-dimethyl-8-phenylxanthines were also synthesized and tested. Introducing a nitro substituent at the 2-position of the 8-substituted phenyl ring resulted in generally low affinity for adenosine receptors (ARs), selectivity toward the A2A subtype was enhanced in some of the compounds. 8-(4-Cyclopentyloxy-5-methoxy-2-nitrophenyl)-1,3-dimethylxanthine (9e) proved to be a potent compound among the 2-nitrophenyl substituted xanthines exhibiting a Ki = 1 µM at human A2A ARs with at least 30 fold selectivity versus human A1 and A2B ARs. Replacement of 8-chloropropoxy phenyl with 8-nitrooxypropoxy phenyl resulted in a negligible change in binding affinity of the 8-substituted xanthines for various AR subtypes. Drug Dev Res 77 : 241-250, 2016. © 2016 Wiley Periodicals, Inc.

Influence of non-covalent modification of multiwalled carbon nanotubes on the crystallization behaviour of binary blends of polypropylene and polyamide 6.

Blends of polypropylene (PP) and polyamide 6 (PA6) with multiwalled carbon nanotubes (MWNTs) were prepared using different processing strategies in a twin-screw micro-compounder. The effect of MWNTs on the crystallization behaviour of the PP phase and the PA6 phase of the blend has been investigated through non-isothermal crystallization studies by differential scanning calorimetric analysis. Furthermore, the effect of the addition of the compatibilizer (PP-g-MA) and the modification of MWNTs (m-MWNTs) with a non-covalent organic modifier (Li-salt of 6 amino hexanoic acid, Li-AHA) has also been studied in context to the crystallization behaviour of the PP and PA6 phase in the blend. The crystallization studies have indicated a significant increase in bulk crystallization temperature of the PP phase in the blend in the presence of MWNTs. Moreover, the formation of 'trans-lamellar crystalline' structure consisting of PA6 'trans-crystalline lamellae' on MWNTs surface was facilitated in the case of blends prepared via 'protocol 2' as compared to the corresponding blends prepared via 'protocol 1'. Wide angle X-ray diffraction analysis has showed the existence of a ß-polymorph of the PP phase due to incorporation of the PA6 phase in the blend. Addition of MWNTs in the blends has facilitated further ß-crystalline structure formation of the PP phase. In the presence of m-MWNTs, a higher ß-fraction was observed in the PP phase as compared to the blend with pristine MWNTs. Addition of PP-g-MA has suppressed the ß-phase formation in the PP phase in the blend. X-ray bulk texture analysis revealed that incorporation of PA6 as well as pristine/modified MWNTs has influenced the extent of orientation of the PP chains towards specific crystalline planes in various blend compositions of PP and PA6.

Dynamics of effluent treatment plant during commissioning of activated sludge process unit.

Industrial effluent treatment plants (ETPs) are very important in protecting the environment and different life forms from harmful industrial waste. Hence, the efficiency of ETPs must be regularly monitored, particularly after major repair or replacement work. Present study evaluated the performance of an ETP over a period of 4 months, during which aeration tank (T1) of the activated sludge unit was replaced with a new one (T2). System had to be maintained operational during this transition, which warranted close monitoring of the system performance due to the daily load of hazardous industrial wastewater. Analysis showed that the raw wastewater was highly variable in composition and contained many hazardous organic and inorganic pollutants, such as heavy metals, bisphenol A and cyanoacetylurea. It showed significant toxicity against HepG2 cells in vitro. However, the ETP was found to successfully treat and detoxify the wastewater. Denaturing gradient gel electrophoresis (DGGE) analysis showed large temporal fluctuations in the ETP microbial community, which is consistent with the variable composition of wastewater. It indicated that functional stability of the ETP was not associated with stability of the microbial community, probably due to high microbial biodiversity and consequently high functional redundancy. In conclusion, the CETP showed consistent level of detoxification and microbial community dynamics after switching to T2, indicating successful development, acclimatization and commissioning of T2.

Synthesis of a new series of 1H-imidazol-1-yl substituted 8-phenylxanthines as adenosine receptor ligands.

A new series of 1H-imidazol-1-yl substituted 8-phenylxanthine analogs has been synthesized to study the effects of the imidazole group on the binding affinity of compounds for adenosine receptors. Competition binding studies of these compounds were carried out in vitro with human cloned receptors using [(3) H]DPCPX and [(3) H]ZM 241385 as radioligands at A(1) and A(2A) adenosine receptors, respectively. The effect of the substitution pattern of the (imidazolyl)alkoxy group on various positions of the phenyl ring at C(8) was also studied. The xanthine derivatives displayed varying degrees of affinity and selectivity towards A(1) and A(2A) receptor subtypes despite a common but variedly substituted Ar-C(8).

Synthesis of 8-(cyclopentyloxy)phenyl substituted xanthine derivatives as adenosine A2A ligands.

The present paper describes the synthesis of a series of 8-(cyclopentyloxy)phenyl-xanthines and their evaluation for affinity for A1 and A2 adenosine receptors using radioligand binding assays. The effects of moving the cyclopentyloxy substituent with or without an ortho methoxy group on the various positions of the 8-phenyl ring have been studied. The vanilloid based xanthines 8-[4-(cyclopentyloxy)-3-methoxyphenyl]-1,3-dimethylxanthine (6a) (K(i)= 100 nM) and 8-[(4-cyclopentyloxy)-3-methoxyphenyl] -3-methyl-1-propylxanthine (12) (K(i) = 150 nM) displayed the highest affinity at A2A receptors as well as over 1000 fold selectivity over the A1 adenosine receptor subtype.

Synthesis of a series of 8-(substituted-phenyl)xanthines and a study on the effects of substitution pattern of phenyl substituents on affinity for adenosine A(1) and A(2A) receptors.

A new series of 8-(substituted-phenyl)xanthines have been synthesized and compounds were evaluated for their affinity for A(1) and A(2) adenosine receptors (AR) using radioligand binding assays. The effects of varying the positions of 8-phenyl substituents on affinity and selectivity at A(1) and A(2A) adenosine receptors have been studied. Isovanilloid 1,3-dimethyl-8-[4-methoxy-3-(2-morpholin-4-ylethoxy)phenylxanthine (9d) displayed the highest affinity and selectivity towards A(2A) AR subtypes with K(i)=100nM over A(1) receptors (Ki>100mM). It has been observed that substitution pattern on 8-phenyl group greatly affects the affinity and selectivity at adenosine receptors, with A(2A) tolerating bulkier substituents than did A(1) receptors.