甲磺酸伊马替尼的合成

以4-甲基-3-硝基苯胺为起始原料,经过缩合、还原、环合等反应制得抗肿瘤药物甲磺酸伊马替尼。并分别讨论了采用无水碳酸钾代替二异丙基乙胺、水合肼和普通催化剂代替铂炭催化剂以及采用异戊醇作为溶剂的优点。最终反应总收率超过50%,用高效液相色谱分析产品纯度在99.5%以上。     

Caffeic Acid Enhances the Anti-Leukemic Effect of Imatinib on Chronic Myeloid Leukemia Cells and Triggers Apoptosis in Cells Sensitive and Resistant to Imatinib

Among the phenolic acids tested on the K562 cell line, a model of chronic myeloid leukemia (CML), caffeic acid (CA) was biologically active on sensitive and imatinib (IM)-resistant cells at micro-molar concentration, either in terms of reduction of cell proliferation or triggering of apoptosis. The CA treatment provoked mitochondrial membrane depolarization, genomic DNA fragmentation and phosphatidylserine exposure, hallmarks of apoptosis. Cell cycle analysis following the treatment with comparable cytotoxic concentrations of IM or CA showed marked differences in the distribution profiles. The reduction of cell proliferation by CA administration was associated with increased expression of two cell cycle repressor genes, CDKN1A and CHES1, while IM at a cytotoxic concentration increased the CHES1 but not the CDKN1A expression. In addition, CA treatment affected the proliferation and triggered the apoptosis in IM-resistant cells. Taken together, these data suggested that CA induced the anti-proliferative effect and triggered apoptosis of CML cells by a different mechanism than IM. Finally, the combined administration of IM and CA at suboptimal concentrations evidenced a synergy of action in determining the anti-proliferative effect and triggering apoptosis. The ability of CA to potentiate the anti-leukemic effect of IM highlighted the nutraceutical potential of CA in CML.     

Pharmacokinetic interaction study of combining imatinib with dasatinib in rats by UPLC–MS/MS

Abstract

This study examined whether oral administration of dasatinib to the rats with imatinib led to any pharmacokinetic interactions. Twenty-four rats were divided randomly into three groups, imatinib group (imatinib 25?mg/kg, n?=?8), dasatinib group (dasatinib 15?mg/kg, n?=?8) and co-administration group (dasatinib 15?mg/kg and imatinib 25?mg/kg, n?=?8). The concentration of imatinib and dasatinib in rat plasma was determined by a sensitive and simple UPLC–MS/MS method. There was statistical pharmacokinetics difference for imatinib in the imatinib group and co-administration group, when co-oral administration imatinib with dasatinib, MRT_(0–t) increased (p?<?0.01). There was statistical pharmacokinetics difference for dasatinib in the dasatinib group and co-administration group, when co-oral administration dasatinib with imatinib, C_max and AUC increased (p?<?0.01), CL and V decreased (p?<?0.01). These data indicate dasatinib could slightly influence the pharmacokinetic profile of imatinib in rats, and imatinib could influence the pharmacokinetic profile of dasatinib in rats, which might cause drug–drug interactions when using imatinib with dasatinib.     

Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs

A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non‐aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane‐ and cubane‐containing analogues were found to possess higher themodynamic solubility, whereas cubane‐ and cyclohexyl‐containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP‐B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off‐target effects.     

Differential effects of ketoconazole,itraconazole and voriconazole on the pharmacokinetics of imatinib and its main metabolite GCP74588 in rat

The aim of the study was to develop a high performance liquid chromatography method for simultaneous determination of imatinib and CGP74588 in rat serum and study the inhibition effects of ketoconazole, itraconazole and voriconazole on pharmacokinetics of imatinib and CGP74588 in rats. In our study, we found that ketoconazole caused a significant increase (63.4%) in the AUC of imainib and a 28.8% increase in C_max, which was greater than that of itraconazole but lower than that of voriconazole. When co-administered with voriconazole, pharmacokinetic parameters of imatinib were not significantly altered except for a 36.8% increase in the C_max of imtinib. The C_max of CGP74588 was decreased by 55.8% and AUC_(0–∞) 49.7%, while the Vz/F and CLz/F values were increased by 1.7-fold and 1.1-fold, respectively. Itraconazole did not significantly influence the pharmacokinetic parameters of imatinib and CGP74588. The difference may be related to the different variation of inhibition sites of the three azole antifungal agents on CYP3A4 and P-gp. In clinical, when imatinib was co-administrated with ketoconazole or voriconazole, dose adjustment of imatinib should be taken into account.     

Synthesis and Characterization of Telmisartan-Derived Cell Death Modulators to Circumvent Imatinib Resistance in Chronic Myeloid Leukemia

New strategies to eradicate cancer stem cells in chronic myeloid leukemia (CML) include a combination of imatinib with peroxisome proliferator-activated receptor gamma (PPARγ) ligands. Recently, we identified the partial PPARγ agonist telmisartan as effective sensitizer of resistant K562 CML cells to imatinib treatment. Here, the importance of the heterocyclic core on the cell death-modulating effects of the telmisartan-derived lead 4′-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid ( 3 b ) was investigated. Inspired by the pharmacodynamics of HYL-6d and the selective PPARγ ligand VSP-51, the benzimidazole was replaced by a carbazole or an indole core. The results indicate no correlation between PPARγ activation and sensitization of resistant CML cells to imatinib. The 2-COOH derivatives of the carbazoles or indoles achieved low activity at PPARγ, while the benzimidazoles showed 60-100 % activation. Among the 2-CO₂CH₃ derivatives, only the ester of the lead ( 2 b ) slightly activated PPARγ. Sensitizing effects were further observed for this non-cytotoxic 2 b (80 % cell death), and to a lesser extent for the lead 3 b or the 5-Br-substituted ester of the benzimidazoles ( 5 b ).     

Sequential Release of Paclitaxel and Imatinib from Core–Shell Microparticles Prepared by Coaxial Electrospray for Vaginal Therapy of Cervical Cancer

To optimize the anti-tumor efficacy of combination therapy with paclitaxel (PTX) and imatinib (IMN), we used coaxial electrospray to prepare sequential-release core–shell microparticles composed of a PTX-loaded sodium hyaluronate outer layer and an IMN-loaded PLGA core. The morphology, size distribution, drug loading, differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, PLGA degradation, cellular growth inhibition, in vivo vaginal retention, anti-tumor efficacy, and local irritation in a murine orthotopic cervicovaginal tumor model after vaginal administration were characterized. The results show that such core–shell microparticles were of spherical appearance, with an average size of 14.65 μm and a significant drug-loading ratio (2.36% for PTX, 19.5% for IMN, w/w), which might benefit cytotoxicity against cervical-cancer-related TC-1 cells. The DSC curves indicate changes in the phase state of PTX and IMN after encapsulation in microparticles. The FTIR spectra show that drug and excipients are compatible with each other. The release profiles show sequential characteristics in that PTX was almost completely released in 1 h and IMN was continuously released for 7 days. These core–shell microparticles showed synergistic inhibition in the growth of TC-1 cells. Such microparticles exhibited prolonged intravaginal residence, a >90% tumor inhibitory rate, and minimal mucosal irritation after intravaginal administration. All results suggest that such microparticles potentially provide a non-invasive local chemotherapeutic delivery system for the treatment of cervical cancer by the sequential release of PTX and IMN.     

人体生物等效性临床试验风险伦理评估要点初探

人体生物等效性试验是评价制剂质量的重要指标。由于已有大量药物有效性和安全性的数据积累,因而其伦理风险往往容易被申办方和伦理委员会所忽视。本文列出了几个具体案例,对人体生物等效性试验中伦理风险提出了几个评估要点,包括：药品说明书中的不良反应;种族差异;健康志愿者和适应症患者不良反应差异等,以期为人体等效性试验的伦理风险控制提供有益的参考。     

Novel Imatinib Derivatives with Altered Specificity between Bcr–Abl and FMS,KIT, and PDGF Receptors

Imatinib is a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl kinase and the PDGF receptor family. Imatinib has revolutionised the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr–Abl and certain solid tumours that harbor oncogenic mutations of the PDGF receptor family. As a leading kinase inhibitor, imatinib also provides an excellent model system to investigate how changes in drug design impact biological activity, which is an important consideration for rational drug design. Herein we report a new series of imatinib derivatives that in general have greater activity against the family of PDGF receptors and poorer activity against Abl, as a result of modifications of the phenyl and N‐methylpiperazine rings. These new compounds provide a platform for further drug development against the therapeutically important PDGF receptor family and they also provide insight into the engineering of drugs with altered biological activity.