三氮唑核苷的不良反应

三氮唑核苷(Ribavirin, 病毒唑,利巴韦林,以下简称Rbv)注射液是广谱抗病毒药,对多种病毒,如疱疹病毒、痘病毒、流感病毒、鼻病毒等均有明显抑制作用。临床上主要用于以上病毒引起的感染。随着临床的广泛使用,其不良反应日趋增多,应引起医务人员的重视。本文对1990～1997年文献报道有关Rbv的55例不良反应进行了统计分类,其中过敏、过敏性休克20例占36.4％;心血管系统6例占10.9％;消化系统5例占9.1％;血液系统20例占36.4％;神经系统3例占5.4％;急性肾功能衰竭1例占1.8％。 1 不良反应的类型及临床表现     

三氮唑核苷致口腔溃疡1例

患者, 女, 35岁, 因左眼疼痛, 于2001年5月28日夜间到我院就诊. 给予氯霉素滴眼液、红霉素眼膏滴眼, 次日病情加重, 双眼睑红肿、 畏光、疼痛, 到五官科门诊就诊, 拟诊断为双眼病毒性角膜炎. 给予无环鸟苷滴眼液, 氯霉素滴眼液, 重组干扰素α1b滴眼液交替滴眼, 每小时1次, 三氮唑核苷注射液(批号2000710)200 mg, im, bid, 三氮唑核苷注射液50 mg加2%普鲁卡因0.5 ml, 双眼球旁注射, qd. 第2天患者病情好转, 但口腔出现不适, 两边颊粘膜粗糙. 第3天嘴唇、两颊红肿, 口腔粘膜溃疡、有滤泡, 烧灼痛, 停止双眼球旁注射治疗, 观察. 第4天双眼疾病明显好转, 而上述不良反应症状加重, 因疼痛张口困难, 不能进食, 疑为三氮唑核苷过敏引起, 即停用.     

三氮唑核苷甘利欣治疗急性乙型肝炎

病毒性肝炎是我国主要传染病之一，乙型肝炎(乙肝)发病率最高，为寻求治疗乙肝的最佳时期，预防肝硬化、肝癌和慢性长期病毒携带的发生，我们在综合治疗的基础上，重点应用三氮唑核苷、甘利欣，经随访临床疗效及预后满意，现就资料完整的100例回顾分析如下：     

酶法生产三氮唑核苷的进展

<正>三氮唑核苷（Ribavirin）化学名为1-β-D呋喃核糖苷-1,2,4-三氮唑-3-甲酰胺（1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide）,其化学结构式为:     

三氮唑核苷治疗秋季腹泻疗效观察

笔者１９９３－１９９４年对我院秋季腹泻病人５１例，采用三氮唑核苷１５－３０ｍｇ／（ｋｇ．ｄ），分３次口服，随机设对照组２０例。结果治疗组的退热及止泻时间明显短于对照组。提示该药口服不失为一种治疗秋季腹泻的有效方法。     

三氮唑核苷合成工艺的改进

本文采用肌苷为原料，经乙酰化后在双（对硝基苯基）磷酸酯的作用下与１，２，４－三氮唑－３－羧酸甲酯缩合，再经氨解制得产品，总收率为４８％，产品符合ＳＱ／ＷＳ－１－１２８２－８１标准。     

Novel quinazolin‐4(3H)‐one linked to 1,2,3‐triazoles: Synthesis and anticancer activity

In this work, a wide range of novel quinazolin‐4(3H)‐one linked to 1,2,3‐triazoles was designed, synthesized, and evaluated against a panel of three human breast (MDA‐MB‐231, MCF‐7, T‐47D), lung (A549), and prostate (PC3) cancer cell lines. Our results revealed that the anticancer activity of the synthesized compounds was selectively affected by the presence of methoxy group on the linker between quinazolinone and 1,2,3‐triazole moieties. According to the calculated IC₅₀ values, compounds 6q , 6w , and 6x showed good cytotoxicity against breast cancer cell lines even more effective than the reference drug, etoposide. Compounds 6q and 6u were found to be potent compounds against A549, non‐small‐cell lung cancer (NSCLC), comparing with erlotinib. Also, the morphological analysis by acridine orange/ethidium bromide double staining test and flow cytometry analysis indicated that potent compounds induced apoptosis in human cancer cell lines. Molecular docking studies were performed to clarify the inhibition mode of compounds 6g , 6u , 6w , and 6x over the EGFR active site. The most promising compounds, 6q and 6u , possessing 3‐methoxy group were well oriented to the gatekeeper hydrophobic pocket of EGFR active site and interact well with Ala719, Val702, and Leu820 through hydrophobic interaction.     

Design and encapsulation of anticancer dual HSP27 and HER2 inhibitor into low density lipoprotein to target ovarian cancer cells

Tumor cells overexpress low-density lipoprotein (LDL) receptors (LDL-r). Hence, LDL is proposed as a targeting shuttle of anticancer drugs. Therefore, the objective of this study was to synthesize a dual inhibitor of heat shock protein 27 (HSP27) and human epidermal growth factor receptor 2 (HER2) conjugated with cholesterol and encapsulated into LDL for selective targeting of ovarian cancer cells. In the present study, the anticancer agent and its cholesterol conjugate were successfully prepared and characterized physically for color, shape, and melting point. Moreover, the compounds were chemically characterized for ¹H NMR and ¹³C NMR spectra using FTIR and LCMS/MS. Our results revealed that the prepared anticancer agent and its cholesterol conjugate elicited dual HSP27 and HER2 inhibition, as confirmed using western blotting. The anticancer agent (compound D) entered cells and targeted the HSP27 function, thereby reducing HER2 expression. However, a cholesterol-conjugated anticancer agent (compound F) had high cellular uptake and inhibited the growth of SKOV3 cells after encapsulation into LDL. The obtained results concluded that the design of an LDL-encapsulated cholesterol-conjugated HSP27-HER2 dual inhibitor may be a promising approach to realize specific targeted achieve killing of ovarian cancer.     

Structural models and binding site prediction of the C-terminal domain of human Hsp90: a new target for anticancer drugs

Heat shock protein 90 is a valuable target for anticancer drugs because of its role in the activation and stabilization of multiple oncogenic signalling proteins. While several compounds inhibit heat shock protein 90 by binding the N-terminal domain, recent studies have proved that the C-terminal domain is important for dimerization of the chaperone and contains an additional binding site for inhibitors. Heat shock protein 90 inhibition achieved with molecules binding to the C-terminal domain provides an additional and novel opportunity to design and develop drugs. Therefore, for the first time, we have investigated the structure and the dynamic behaviour of the C-terminal domain of human heat shock protein 90 with and without the small-middle domain, using homology modelling and molecular dynamics simulations. In addition, secondary structure predictions and peptide folding simulations proved useful to investigate a putative additional alpha-helix located between H18 and beta20 of the C-terminal domain. Finally, we used the structural information to infer the location of the binding site located in the C-terminal domain by using a number of computational tools. The predicted pocket is formed by two grooves located between helix H18, the loop downstream of H18 and the loop connecting helices H20 and H21 of each monomer of the C-terminal domain, with only two amino acids contributing from each middle domain.     

Retaspimycin hydrochloride (IPI-504): a novel heat shock protein inhibitor as an anticancer agent

Heat shock proteins are vital to cell survival under conditions of stress. They bind client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes and recovery of proteins from aggregates. Heat shock protein inhibitors are a diverse group of novel agents that have been demonstrated to have pro-apoptotic effects on malignant cells through inhibition of ATP binding on the ATP/ADP-binding pocket of the heat shock protein. Initial development of heat shock protein 90 inhibitors, geldanamycin and 17-AAG, were limited by hepatotoxicity and the need for solvent carrying agents. In contrast, retaspimycin, or IPI-504, a derivative of geldanamycin and 17-AAG, is highly soluble in water and generally well tolerated. In Phase I/II trials, retaspimycin has shown activity in NSCLC and gastrointestinal stromal tumor. The most promising activity was observed in gastrointestinal stromal tumors. Phase I/II trials are currently underway to evaluate the dosing schedules and activity of IPI-504 in breast cancer. Given the in vitro activity in diffuse large B-cell lymphoma, mantle cell lymphoma, melanoma, leukemia and pancreatic cancer, current and future trials are of clinical interest. This article reviews IPI-504 and its utility in a wide variety of cancer phenotypes.     

The role of reduced intracellular concentrations of active drugs in the lack of response to anticancer chemotherapy

A major difficulty in the treatment of cancers is the poor response of many tumors to pharmacological regimens. This situation can be accounted for by the existence of a variety of complex mechanisms of chemoresistance （MOCs）, leading to reduced intracellular concentrations of active agents, changes in the molecular targets of the drugs, enhanced repair of drug-induced modifications in macromolecules, stimulation of anti-apoptotic mechanisms, and inhibition of pro-apoptotic mechanisms. The present review focuses on alterations in the expression and appearance of the genetic variants that affect the genes involved in reducing the amount of active agents inside tumor cells. These alterations can occur through two mechanisms： either by lowering uptake or enhancing efflux （so-called MOC-1a and MOC-1b, respectively）, or by decreasing the activation of prodrugs or enhancing inactivation of active agents through their biotransformation （MOC-2）. The development of chemosensitizers that are useful in implementing the pharmacological manipulation of these processes constitutes a challenge to modern pharmacology. Nevertheless, the important physiological roles of the most relevant genes involved in MOC-1a, MOC-1b, and MOC-2 make it difficult to prevent the side effects of chemosensitizers. A more attainable goal in this area of pharmacological enquiry is the identification of proteomic profiles that will permit oncologists to accurately predict a lack of response to a given regimen, which would be useful for adapting treatment to the personal situation of each patient.     

Enzymatic phosphorylation of acyclic nucleoside analogs and correlations with antiherpetic activities

The inhibitor and substrate specificities of deoxythymidine (dThd) kinase purified from herpes simplex virus (HSV Type 1) were studied. A number of nucleosides and nucleoside analogs were phosphorylated by the virus coded enzyme. These included several compounds structurally related to 9-(2-hydroxyethoxymethyl)guanine (acyclovir), a potent inhibitor of HSV replication. Some contained guanine with 9-substituents differing from that of acyclovir by methylene additions, methylene and thioether substitutions for the ether oxygen, and branching on the distal side of the ether oxygen. Others were various 2-substituted 6-hydroxypurines with the 9-(2-hydroxyethoxymethyl) substituent. A limitation of the specificity of the enzyme with guanine derivatives was the lack of phosphorylation of any derivative with an acyclic moiety branched on the proximal side of the ether oxygen. Many of the compounds that were phosphorylated were subsequently found to inhibit HSV replication. Such compounds apparently inhibited HSV replication via the same route of activation previously described for acyclovir [G. B. Elion, P. A. Furman, J. A. Fyfe, P. de Miranda, L. Beauchamp and H. J. Schaeffer, Proc. natn. Acad. Sci. U.S.A.74, 5716 (1977)]. Moreover, several compounds not phosphorylated by the enzyme did not inhibit replication. However, some other acyclic nucleoside analogs that were phosphorylated were not good antivirals, indicating that phosphorylation catalyzed by the HSV dThd kinase was not sufficient for inhibition of viral replication to occur. These results emphasize the importance of the specificity of cellular kinases and the HSV DNA polymerase to the mechanism of antiviral activity. The dThd kinase from Vero cells was also purified. With this host cell enzyme, kinetic constants of known antiviral compounds were determined and compared to those of dThd (relative V′_max; k′_m): dThd (100; 1.3 μM), 5-iodo-2′-deoxyuridine (87; 1.8 μM), 5-trifluoromethyl-2′-deoxyuridine (91; 1.2 μM), 5-bromo-2′-deoxycytidine (5; 580 μM), and 9-β-d-arabinofuransoylthymine (23; 2300 μM). None of the purine acyclic nucleoside analogs tested (at 1000 μM) was detectably phosphorylated by the Vero cell enzyme, and all had apparent K_i values >300 μM. The phosphorylation catalyzed by host cell dThd kinase correlated with the toxicity of some pyrimidine nucleoside analogs.     

Synthesis,molecular modeling,in vivo study,and anticancer activity of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen

A new series of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen ( 7a–m ) was synthesized in this study. The structures of these compounds were characterized by spectral (Fourier‐transform infrared spectroscopy, ¹H‐nuclear magnetic resonance (NMR), ¹³C‐NMR, and high‐resolution electron ionization mass spectrometry) methods. Furthermore, molecular modeling of these compounds was studied on human methionine aminopeptidase‐2. All synthesized compounds were screened for anticancer activity against three prostate cancer cell lines (PC3, DU‐145, and LNCaP) using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium colorimetric method. Compound 7a showed the best activity against the PC3, DU‐145 and LNCaP cancer cell lines with IC₅₀ values of 26.0, 34.5, and 48.8 μM, respectively. Compounds 7b , 7k , and 7m showed anticancer activity against cancer cell lines PC3 and DU‐145 with IC₅₀ values of 43.0, 36.5, 29.3 μM and 49.8, 49.1, 31.6 μM, respectively. Compounds 7f and 7g showed anticancer activity against PC3 cells with IC₅₀ values of 43.4 and 34.5 μM, respectively. To assess the biodistribution in mice of IRDye800, dye‐labeled compound 7a or 100 μM of free dye was injected intravenously into the mice's tail. In vivo images were taken with in vivo imaging system spectrum device at 60, 120, 180, 240, 300, and 360 min after injection. At the end of 360 min, ex vivo studies were carried out to determine in which organs the dye was accumulated in the urogenital system. Ex vivo studies showed that the accumulation of compound 7a in the prostate is greater than that of the free dye, and it is concluded that compound 7a may be promising for the treatment of prostate cancer.     

雷公藤甲素治疗胰腺癌的研究进展

胰腺癌是一种消化道常见恶性肿瘤之一,预后差,诊断期较晚。雷公藤甲素是雷公藤中有效成分之一,具有显著的药理活性。雷公藤甲素可通过抑制细胞周期和增殖、诱导细胞凋亡、抑制细胞迁移和侵袭、调节肿瘤血管生成、协同其他药物抗耐药、抑制热休克蛋白相关基因、诱导自噬等多种途径治疗胰腺癌。总结了雷公藤甲素治疗胰腺癌的药理作用及其作用机制的研究进展,为雷公藤甲素成为胰腺癌治疗的候选药物提供依据。     

Discovery and development of heat shock protein 90 inhibitors as anticancer agents: a review of patented potent geldanamycin derivatives

Introduction: There has been research on anticancer strategies which focus on disrupting a single malignant protein. One of the strategies is the inhibition of one protein, heat shock protein 90 (Hsp90). There are many reasons why Hsp90 protein is targeted by anticancer agents: maintenance of cellular homeostasis in organisms involves Hsp90 and its client proteins; moreover, Hsp90 complex is involved in regulating several signal transduction pathways and plays an important role in the maturation of lots of tumor-promoting client proteins. Geldanamycin (GM), the first benzoquinone ansamycin, has shown anticancer activity by binding to Hsp90. Currently, several GM derivatives such as 17-AAG, 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin, IPI-493, and IPI-504 are being progressively developed toward clinical application.

Areas covered: Several research groups have studied GM and its derivatives to develop novel and potent Hsp90 inhibitors for the treatment of cancer. The crystal structure of Hsp90 was utilized to undergo structural optimization of GM derivatives. A wide variety of structural modifications were performed and some of the derivatives are now in clinical studies. The aim of this review was to summarize and analyze the structure-activity relationships of GM derivatives and the focus is on patented novel and pharmaceutically efficacious derivatives published from 1971 to 2012.

Expert opinion: Hsp90 inhibitors offer an effective therapeutic approach for treatment of cancer. To date, the clinical results of 17-AAG, IPI-493, and IPI-504 suggest that these GM derivatives could be used either alone or in combination with other marketed medications for the treatment of cancer patients. As there are not any marketed Hsp90 inhibitors, inhibiting Hsp90 chaperone function remains as a promising strategy that still requires further research.     

Biscoumarin–pyrimidine conjugates as potent anticancer agents and binding mechanism of hit candidate with human serum albumin

In our continuing efforts to develop therapeutically active coumarin‐based compounds, a series of new C4–C4′ biscoumarin–pyrimidine conjugates ( 1a–l ) was synthesized via S_N2 reaction of substituted 4‐bromomethyl coumarin with thymine. All compounds were characterized using spectroscopic techniques, that is, attenuated total reflection infrared (ATR‐IR), CHN elemental analysis, and ¹H and ¹³C NMR (nuclear magnetic resonance). In addition, the structure of compound 1d (1,3‐bis[(7‐chloro‐2‐oxo‐2H‐chromen‐4‐yl)methyl]‐5‐methylpyrimidine‐2,4(1H,3H)‐dione) was established through X‐ray crystallography. Compounds 1a–l were screened for in vitro anticancer activity against C6 rat glioma cells. Among the screened compounds, 1,3‐bis[(6‐chloro‐2‐oxo‐2H‐chromen‐4‐yl)methyl]‐5‐methylpyrimidine‐2,4(1H,3H)‐dione ( 1c ) was identified as the best antiproliferative candidate, exhibiting an IC₅₀ value of 4.85 μM. All the compounds ( 1a – l ) were found to be nontoxic toward healthy human embryonic kidney cells (HEK293), indicating their selective nature. In addition, the most active compound ( 1c ) displayed strong binding interactions with the drug carrier protein, human serum albumin, and exhibited good solution stability at biological pH conditions. Fluorescence, UV–visible spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism of compound 1c with protein.