前药原理在药物研究中的应用与进展

前药具有提高生物利用度,增加水溶性,减少不良反应等特性,在保持或增强原药药效的同时又克服了原药的缺点。本文主要综合前药原理在药物研究中的典型实例,介绍前药原理在药物研究中的应用。     

抗肿瘤前药在肿瘤靶向治疗中的新进展

化疗是临床上治疗肿瘤的主要途径之一,但化疗药物在肿瘤部位的低浓度及系统毒性仍是其临床应用受限的首要问题。前体药物通过对原药的化学结构或药物剂型给予一定修饰,大大克服了化疗药物的缺点,开辟了一条靶向治疗肿瘤的新途径。目前,新发展的抗肿瘤前药有导向酶活化前药、载体前药、脂质前药等,现对其研究进展和应用做一综述。     

新药研究中的前药原理

前药具有改变药物的理化性质 ,提高生物利用度 ,增加水溶性 ,减少不良反应 ,定位到达靶器官等特性。前药保持或增强原药的药效 ,同时又克服了原药的缺点。本文主要综合前药原理在新药设计中的典型实例 ,介绍前药原理的应用规律     

前药载体研究新进展

<正>前体药物(Prodrug),是指一种口服后经体内化学或酶代谢,能释放出有药效活性的代谢物或原药的化合物。它将原药与一种载体经化学键连接,形成暂时的化学结合物或覆盖物,从而修饰或改变原药的理化性质,经体内降解发挥其药效。前药已经在药物结构修饰及化学发展中发挥了巨大的作用,将成为21世纪药物设计与开发的重要手段。前药结构通常分为原药和载体两部分,前药设计就是在原药最适宜的功能基上键合载体分子。这个键合过程要求能在实     

前体药物制备研究进展

药物的药效取决于药物的化学结构,也受到剂型和给药途径的影响。药物的作用是多方面的,有副作用,也有或高或低的毒性。为了使一种药物能充分发挥作用,克服其生物学和药学方面的缺点,可以采用制备前体药物的方法,即对其化学结构进行化学修饰,改变其理化性质,从而改善其吸收、分布和排泄,以克服其缺点,有利于药效的充分发挥。药物制成前体药物后,对药物作用的改善已有不少综述,本文按药物结构讨论     

铂类抗肿瘤药物的研究进展

目的综述铂类抗肿瘤药物的作用机制及新型铂类抗肿瘤药物的设计策略。方法查阅国内外近10年相关文献,对其进行归纳、总结,从铂类抗肿瘤药物的研究概况、作用机制及新型药物的设计策略几方面进行了介绍。结果铂类药物在抗肿瘤领域发挥着重要作用,为解决现有药物存在的耐药性、组织毒性等缺点,靶向给药、Pt(Ⅳ)模式前药、单功能团铂类抗肿瘤药物等更先进的设计策略越来越受到重视。结论铂类药物及新型铂类药物仍是抗肿瘤药物的研究热点,值得进一步研究开发。     

喜树碱及其衍生物的前药研究进展

分类综述喜树碱及其衍生物的水溶性和脂溶性前药的研究进展。喜树碱类抗肿瘤药物是抗肿瘤药物研究领域的热点之一。鉴于喜树碱及其衍生物的毒副作用和E内酯环的不稳定性,制备其前药,则能克服这些缺点,并可改善药物动力学特征,提高其溶解性和肿瘤靶向性。     

水溶性紫杉醇前药的制备及抗肿瘤活性的研究

目的紫杉醇是具有良好抗肿瘤疗效的化学药物,由于紫杉醇本身化学结构复杂,难溶于水,在一定程度上限制了紫杉醇药物在临床上的广泛应用,因此改善紫杉醇水溶性是解决紫杉醇药物不足的关键问题。方法本实验选用水溶性叶酸配体作为"导向基团",谷氨酸为连接叶酸和紫杉醇的Linker,氨基PEG(MW:350)为药物增溶剂和稳定剂,制备水溶性叶酸-PEG-谷氨酸-紫杉醇前药。用LC-MS鉴定前药的化学结构,通过对前药溶解性及释药动力学曲线的测定,确定前药的理化性质。用MTT实验分析并对比紫杉醇原药与前药在不同肿瘤细胞(MCF-7、MDA-MB-231、A549)和正常细胞HELF(人胚肺成纤维细胞)中的毒性和药效作用。用荧光标记法直观观察紫杉醇前药在肿瘤细胞和组织中的靶向性。结果实验结果证明已成功合成叶酸-PEG-谷氨酸-紫杉醇前药,并具有较好的溶解性和原药释放动力学曲线,细胞实验表明在叶酸受体-配体作用的介导下,叶酸-PEG-谷氨酸-紫杉醇前药靶向叶酸受体高表达的肿瘤细胞,减少对叶酸受体低表达正常细胞的毒副作用。结论叶酸-PEG-谷氨酸-紫杉醇前药具有良好的抗肿瘤活性。     

以胆酸为载体的肝靶向抗肿瘤药物的研究

胆酸是一类具有广阔前景的肝靶向载体，抗肿瘤药物与胆酸偶联后，可以增加药物的肝吸收，降低药物的毒副作用，同时保留甚至增强药物的抗肿瘤活性，其中一些偶联物还能克服原药的耐药性。笔者主要介绍以胆酸为载体的肝靶向抗肿瘤药物的机制及应用，重点介绍胆酸-铂螯合物的研究情况。     

苏联抗肿瘤药物临床前的研究

抗肿瘤抗生素或其它抗肿瘤药物在临床前必须进行认真的临床前研究,特别是毒理学和药理学方面的研究。     

Synthesis and biological properties of oxazolinodaunorubicin—a new derivative of daunorubicin with a modified daunosamine moiety

Oxazolinodaunorubicin, a new daunorubicin derivative with a modified daunosamine moiety, was synthesized. The biological properties of this derivative and the parent daunorubicin were compared. The results showed antiproliferative activity of the derivative with significantly lower toxicity (an LD₅₀ value ca. 20 times higher than that of parent daunorubicin) and an ability to completely overcome the resistance of cancer cells to this drug in vitro. Cardiotoxicity determination using male mice treated with a single dose of 75% of the LD₅₀ value indicated that the cardiotoxicity of new analog was much lower than that of the parent drug. Preliminary results in transplanted murine tumor models revealed that a single-dose injection of the tested compounds exhibited antitumor activity in P388 and L1210 leukemia and 16/C mammary adenocarcinoma bearing mice.     

胆汁酸衍生物的抗肿瘤作用研究进展

综述具有抗肿瘤作用的胆汁酸衍生物的研究进展。胆汁酸是体内胆固醇代谢产生的甾体化合物,为脂类及脂溶性维生素消化吸收所必需。其因具有独特的化学结构和肝肠循环特性,不但易于进行结构修饰,而且可作为理想的药物载体,实现肝肠靶向给药,提高生物利用度及代谢稳定性,降低毒副作用。     

Comparative in vitro study of the effects of the new antitumor drug Ukrain and several cytostatic agents on the thiol groups in the tissue of Guerin carcinoma and its resistance to cisplatin variant

A comparative in vitro study between the effects of Ukrain (a new synthetic thiophosphoric acid derivative of great celandine alkaloids) and alkylating antitumor drugs cyclophosphamid and cisplatin on total thiol content in Guerin carcinoma, Guerin/cis-DDP carcinoma, and in animal livers was carried out. It is shown that Ukrain action on thiol groups in Guerin carcinoma tissue does not differ from that of cyclophospamid and cisplatin to both of which Guerin carcinoma is very sensitive. Once tumor resistance to cisplatin has developed, cisplatin does not react with tumor thiol groups and cyclophosphamid reactions with tumor thiol groups decrease. Reactions of Ukrain with thiol groups of cisplatin resistant tumors increase. This indirectly indicates the increase of tumor sensitivity to this drug. Therefore, the cytotoxicity of Ukrain is similar to that of known antitumor drugs and can probably overcome the cisplatin resistance of the tumor.     

Prodrugs as therapeutics

Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations. The patent literature shows a dramatic increase in numbers of prodrug patents (> 2000% increase in 2002 compared to 1993), with claims for cancer treatment comprising 37% of these. This increase is largely due to the rise from North American-based multinationals and some smaller drug delivery companies mirroring the overall trend. In 2001 and 2002, 14% of all new approved chemical drugs were prodrugs. It appears that prodrugs to overcome barriers to the delivery of problematic drug candidates are becoming an integral part of the drug discovery paradigm.     

Antitumor activity of new liposomal prodrug of mitomycin C in multidrug resistant solid tumor: insights of the mechanism of action

The antitumor activity of a novel thiolytically cleavable lipid-based prodrug of mitomycin C (MMC) delivered by STEALTH liposomes (SL) was studied in drug resistant human ovarian carcinoma A2780/AD model and compared with free MMC and both free and SL forms of an established anticancer drug--doxorubicin (DOX). It was found that SL-prodrug (SL-pMMC) possessed enhanced antitumor activity when compared with the parent MMC, free DOX, and SL-DOX. An observance of the high antitumor efficiency of SL-pMMC was a result of its preferential accumulation in the tumor by the enhanced permeability and retention (EPR) effect, suppression of multidrug resistance (MDR) associated with P-glycoprotein and MRP drug efflux pumps, activation of caspase-dependent apoptosis signaling pathways and suppression of antiapoptotic cellular defense by increasing the BAX/BCL2 ratio. Consequently, the described SL-pMMC formulations can be considered good candidates for the chemotherapy of multidrug resistant tumors.     

Antitumor activity of new liposomal prodrug of mitomycin C in multidrug resistant solid tumor: Insights of the mechanism of action

The antitumor activity of a novel thiolytically cleavable lipid-based prodrug of mitomycin C (MMC) delivered by STEALTH® liposomes (SL) was studied in drug resistant human ovarian carcinoma A2780/AD model and compared with free MMC and both free and SL forms of an established anticancer drug—doxorubicin (DOX). It was found that SL-prodrug (SL-pMMC) possessed enhanced antitumor activity when compared with the parent MMC, free DOX, and SL-DOX. An observance of the high antitumor efficiency of SL-pMMC was a result of its preferential accumulation in the tumor by the enhanced permeability and retention (EPR) effect, suppression of multidrug resistance (MDR) associated with P-glycoprotein and MRP drug efflux pumps, activation of caspase-dependent apoptosis signaling pathways and suppression of antiapoptotic cellular defense by increasing the BAX/BCL2 ratio. Consequently, the described SL-pMMC formulations can be considered good candidates for the chemotherapy of multidrug resistant tumors.     

Active metabolites resulting from decarboxylation, reduction and ester hydrolysis of parent drugs

Decarboxylation, reduction and hydrolysis can yield active metabolites from the parent drug. Major therapeutic indications and metabolic routes of these drugs are reviewed. Changes in the logP values (determined and calculated) from the parent drug to the active metabolite show certain characteristics in comparison to other phase I metabolic alterations. Metabolic decarboxylation of parent drug is commonly associated with increase in lipophilicity. However, in some cases, decarboxylation may cause a reduction in lipophilicity. Ester hydrolysis generally unmasks either the polar carboxylic or hydroxyl group with the outcome of an increase in hydrophilicity. On the contrary, hydrolysis of phosphate ester means a huge increase in the lipophilic character of the drug, as the highly polar phosphate group is removed.