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Chinese Chemical Letters 2023年第6期34卷 306-309页

作者： Chenglong Feng Xin Liu Yuanbin She Zhenlu Shen Meichao Li College of Chemical Engineering Zhejiang University of TechnologyHangzhou 310032China

A facile and elegant method for synthesis of novel N-aryl phenothiazine derivatives from 2-phenylindolizines and phenothiazines through direct electrochemical oxidation has been *** approach was performed smoothly at room temperature without external oxidant and *** voltammetry and in situ FTIR techniques were applied to analyze the cross-coupling process of phenothiazines and 2-phenylindolizines,which helped to select the appropriate reaction *** the optimized conditions,a broad range of substrates were well tolerated,affording the desired products in moderate to excellent isolated yields(up to 91%)with high ***,a plausible mechanism involving a radical pathway has been proposed.

关键词： N-Aryl phenothiazine derivatives Electrochemical oxidation 2-Phenylindolizines phenothiazines Cross-coupling

Modulating multidrug resistance through inhibiting of protein kinase C activity by phenothiazines

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Chinese Science Bulletin 1998年第14期43卷 1196-1200页

作者： Wei Liang Chunzheng Yang Jing Qi Hui Peng Jianrong Duan Hanzhi Liu Dexian Zheng Chinese Acad Med Sci State Key Lab Expt Hematol Tianjin 300020 Peoples R China Peking Union Med Coll Tianjin 300020 Peoples R China

In the present study, actions of phenothiazines(PTZ) in reversing multidrug resistance(MDR) and inhibiting PKC activity were investigated. It was found that the three PTZs caused 2.49, 36.58 and 75.78 fold reversal of K562/AO2 MDR cells resistant to adriamycin, respectively, while the chemosensitizer verapamil caused 40 fold reversal in the same condition, indicating that PTZ11 is a novel reversal agent of MDR and a potential chemotherapeutic reagent for tumor therapy. PKC activity analysis in the presence of PTZs showd that PTZ6 and PTZ11 inhibited rat brain protein kinase C activity in a manner of dose_dependent. The IC 50 values were (489.77±31.4) and (113±9.64) μmol/L, respectively. PTZ7 had no inhibition on PKC activity. Further study showed that PTZ11 could reduce PMA_mediated activation of PKC in a manner of dose_dependent, suggesting that PTZ11 might compete for the high_affinity phorbol ester binding site within PKC molecule. Recently, an X_ray structure of PMA in complex with PKC Cys2 activator_binding domain was solved. We therefore decided to explore the possible binding model of PTZ11 with PKC molecule using SYBYL 6.02 program. It was shown that the binding site of PTZ11 with PKC molecule partially overlapped with that of PMA, providing for the first time new data for designing PKC inhibitors and MDR reversal drugs.

关键词： protein kinase C multidrug resistance phenothiazines molecular modeling.

Structure-activity Relationship of phenothiazines for Inhibition of Protein Kinase C and Reversal of Multidrug Resistance

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Journal of Chinese Pharmaceutical Sciences 2002年第2期11卷 11-18页

作者：彭晖杨纯正齐静梁巍黄牛郭宗儒中国医学科学院中国协和医科大学血液学研究所实验血液学国家重点实验室天津300020 中国医学科学院中国协和医科大学药物研究所北京100050

Studies on structure-activity relationship of phenothiazines (PTZs) forinhibition of protein kinase C (PKC) and reversal of multidrug resistance (MDR) has been made invitro. The results showed that the order of potency of reversal effect of PTZs on MDR is as follows:2-COC_3 H_7 > 2-CF_3 > 2-COCH_3 > H. The type of piperazinyl substitution also significantlyaffected potency against MDR. The results show the order: CH_3 > COOC_2 H_5 > C_2 H_4 OH. Inaddition, PKC plays a marked role in diverse cellular process including MDR. Some derivatives of PTZwas tested for inhibition of PKC, of which PTZ11 showed the highest inhibitory effect of MDR andPKC, implying a potential reversal agent of MDR for tumor therapy in the future. We also tried toexplore the possible binding model of PTZs to PKC. Our molecular-modeling study preliminarilysuggests how these PTZs bind to PKC and provides a structural basis for the design of high affinityPKC-modulator. The infor-mation may be used in the rational design of more effective drugs.

关键词： phenothiazines multidrug resistance molecular modeling protein kinase C

Potential antitumor mechanisms of phenothiazine drugs

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Science China(Life Sciences) 2013年第11期56卷 1020-1027页

作者： QI Lu DING YanQing Department of Pathology School of Basic Medical Sciences Southern Medical University Department of Pathology Nanfang Hospital Southern Medical University

In this study,three kinds of phenothiazine drugs were analyzed to explore their potential antitumor ***,target proteins that could interact with chlorpromazine,fluphenazine and trifluoperazine were ***,the target proteins of the three drugs were *** signaling pathway enrichment and related disease enrichment were conducted for the intersected proteins to extract the enrichment categories associated with *** regulation network analysis of the protein interactions,the mechanisms of action of these target proteins in tumor tissue were clarified,thus confirming the potential antitumor mechanisms of the phenothiazine *** final results of cell signaling pathway enrichment and related disease enrichment showed that the categories with the highest score were all found in *** proteins belonging to the tumor category included signaling pathway members such as Wnt,MAPK and retinoic acid ***,another target protein,MAPK8,could indirectly act on target proteins CDK2,IGF1R,GSK3B,RARA,FGFR2 and MAPK10,thereby affecting tumor cell division and ***,phenothiazine drugs may have potential antitumor effects,and tumorassociated target proteins play important roles in the process of cell signaling transduction cascades.

关键词： phenothiazines antitumor bioinformatics target proteins

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Phenothiazine vs 5HT3 Antagonist Prophylactic Regimens to Prevent Post‐Anesthesia Care Unit Rescue Antiemetic: An Observational Study

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Open Journal of Anesthesiology 2015年第2期5卷 27-32页

作者： Joseph R. Ruiz Joe E. Ensor Jeffrey W. Lim Antoinette Van Meter Thomas F. Rahlfs Department of Anesthesiology and Perioperative Medicine The University of Texas MD Anderson Cancer Center Houston USA Department of Biostatistics The University of Texas MD Anderson Cancer Center Houston USA

Purpose: Our practitioners are asked to consider a patient’s postoperative nausea and vomiting (PONV) risk profile when developing their prophylactic antiemetic strategy. There is wide variation in employed strategies, and we have yet to determine the most effective PONV prophylactic regimen. The objective of this study is to compare prophylactic antiemetic regimens containing: phenothiazines to 5HT3 antagonists for effectiveness at reducing the incidence of Post‐Anesthesia Care Unit (PACU) rescue antiemetic administration. Methods: This is an observational study of 4392 nonsmoking, women who underwent general anesthesia for breast surgery from 1/1/2009 through 6/30/2012. Previous history of PONV or motion sickness (HxPONV/MS) and the use of PACU opioids were recorded. Prophylactic antiemetic therapy was left to the discretion of the anesthesia care team. We compared phenothiazines and 5HT3 antagonists alone and with a glucocorticoid to determine the most effective treatment regimen in our practice for the prevention of the administration of PACU rescue antiemetics. Results: Patients who received a phenothiazine regimen compared to a 5HT3 antagonist regimen were less likely to have an antiemetic administered in the PACU (p = 0.0100) and this significant difference in rates holds in a logistic regression model adjusted for HxPONV/MS and PACU Opioid use (p = 0.0103). Conclusions: Based on our findings our clinicians are encouraged to administer a combination of a phenothiazine and a glucocorticoid in female, nonsmoking surgical breast patients for the prevention of PACU rescue antiemetic administration.

关键词： phenothiazines 5HT3 Antagonists Prophylactic Antiemetics PACU Antiemetic Administration

Evaluation of the Anti-Trypanosoma cruzi Effects of the Antipsychotic Drug Levomepromazine

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International Journal of Clinical Medicine 2012年第5期3卷 344-351页

作者： Inga Eva Stik Lange Elisabeth Mieko Furusho Pral Anahi Magdaleno Ariel Mariano Silber Departamento de Parasitologia Instituto de CienciasUniversidade de Sao PauloSao PauloBrazil

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a relevant parasitic disease in the Americas. Current chemotherapy relies on Nifurtimox and Benznidazole, which present serious drawbacks, including high toxicity, low efficiency and the emergence of resistant strains. In the present work, the perspectives of levomepromazine, a tri-cyclic compound belonging to the family of phenotiazines with well-known properties as antipsychotics were evaluated as a potential anti-T. cruzi drug. We show that this drug is able to inhibit the proliferation of epimastigotes (IC50 = 0.41 ± 0.01 mM) and to interfere with the infection of the host cells (IC50 = 0.34 ± 0.01 mM). Interestingly, the treatment with levomepromazine affected the ability of metabolites such as glucose, proline and glutamate to fuel the recovery of epi-mastigotes after being submitted to metabolic stress. These findings prompt levomepromazine as a promising leader drug to obtain new trypanocidal activities.

关键词： Chagas Disease phenothiazines Trypanothione Reductase Amino Acid Metabolism Chemotherapy

固相萃取-紫外导数光谱法测定人及家兔组织检材中吩噻嗪类药物含量

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固相萃取-紫外导数光谱法测定人及家兔组织检材中吩噻嗪类药物含量