SYNTHESIS AND IN-SILICO ANTI-INFLAMMATORY INVESTIGATION OF 2, 3-DIHYDROCHROMEN-4-ONE AND 3, 4-DIHYDROBENZO[B]OXEPIN-5(2H)-ONE BASED PYRAZOLE DERIVATIVES

This study synthesized six pyrazole derivatives from the key intermediates 2,3-dihydrochromen-4-one and 3,4-dihydrobenzo[b]oxepin-5(2H)-one. We have characterized all pyrazole derivatives as well as conducted in silico anti-inflammatory studies. The DFT calculations were performed using Gaussian 09 software. The compound 9 has the lowest energy gap (∆E, 1.0698 eV), lowest hardness (0.5349 eV), highest softness (1.8695 eV), and highest electrophilicity (7.0809eV) among all pyrazole derivatives and standard Aspirin. Swiss ADME software was used to carry out the ADME analysis. The chloro-substituted pyrazole derivatives (5, 6, and 9) were non-toxic, however, the nitrogen-substituted pyrazole derivatives (10, 13 and 14) and Aspirin were toxic. The docking patterns of the pyrazole derivatives with COX-2 selective inhibitors proteins (5F19) have been studied. Compound 9 has the lower binding energy (-10.2Kcal/mol) as compared with that of other pyrazole derivatives and standard Aspirin drugs. As a result, the pyrazole derivatives compound 9 is a promising anti-inflammatory drug with selective COX-2 inhibition as compared to the Aspirin drugs physicochemical properties

Inhibition of heat shock protein 90 with AUY922 represses tumor growth in a transgenic mouse model of islet cell neoplasms

Background: This study was designed to evaluate the role of heat shock protein 90 (HSP90) in tumor progression of murine islet cell tumors. Blockade of HSP90 has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with AUY922, a newly developed HSP90 inhibitor, have not been examined. Material and Methods: The carcinoid cell line BON-1 and the HSP90 inhibitor AUY922 were used to determine effects on signaling and growth in vitro. In vivo transgenic RIP1-Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or AUY922 (25 mg/kg/twice per week) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by immunohistochemistry. Quantitative real-time PCR was performed for HSP90 targets with RNA from islets isolated from treated and untreated RIP1-Tag2 mice. Results: HSP90 blockade impaired constitutive and growth factor-induced signaling in vitro. Moreover, HSP90 inhibition attenuated in vitro cell growth in a dose-dependent manner. In vivo, AUY922 significantly reduced tumor volume by 92% compared to untreated controls (p = 0.000), and median survival in the used transgenic mouse model was prolonged (110 vs. 119 days; p = 0.75). Quantitative real-time PCR for downstream target genes of HSP90 demonstrated significant downregulation in the islet cell tumors of RIP1-Tag2 mice treated with AUY922, confirming our ability to achieve effective pharmacologic levels of AUY922 within the desired tissue site in vivo. Conclusion: This is the first study to show that the HSP90 antagonist AUY922 may provide a new option for therapy of islet cell neoplasms

Malignant fibrous histiocytoma of the distal femur after an arthroscopic anterior cruciate ligament reconstruction: A case report and a review of the literature

<p>Abstract</p> <p>Background</p> <p>Malignant degeneration in association with orthopaedic implants is a known but rare complication. To our knowledge, no case of osseous malignant fibrous histiocytoma after anterior cruciate ligament reconstruction is reported in the literature.</p> <p>Case presentation</p> <p><b>We report a </b>29-year-old male Turkish patient who presented with severe pain in the operated knee joint 40 months after arthroscopic anterior cruciate ligament reconstruction. X-ray and MR imaging showed a large destructive tumor <b>in </b>the medial femoral condyle. Biopsy determined a malignant fibrous histiocytoma. After neoadjuvant chemotherapy, wide tumor resection and distal femur reconstruction with a silver-coated non-cemented tumor knee joint prosthesis was performed. Adjuvant chemotherapy was continued according to the EURAMOS 1 protocol.</p> <p>Conclusions</p> <p>Though secondary malignant degeneration after orthopaedic implants or prostheses is not very likely, the attending physician should take this into consideration, especially if symptoms worsen severely over a short period of time.</p