大豆苷元的前药修饰研究进展

大豆异黄酮大豆苷元具有抗氧化、心血管保护、抗癌、抗炎、抗溃疡及雌激素等多种药理功能.本文综述了大豆苷元的化学修饰研究进展,为充分利用大豆资源和发展以大豆苷元为先导物的化学活性修饰物提供研究信息.     

Novel Synthesis of Fosphenytoin: Anti-Convulsant Prodrug

A simple, new synthesis of fosphenytoin sodium 1, a prodrug, via imidate ester and employing mild reaction conditions is described.     

酯类前药阿魏酸丹皮酚酯的合成

以阿魏酸和丹皮酚为起始原料，先将阿魏酸的羟基用乙酰基保护得乙酰阿魏酸（1）； 1与丹皮酚经酯化反应制得乙酰阿魏酸丹皮酚酯（2）； 2在水合肼催化下水解脱去保护基合成了酯类前药阿魏酸丹皮酚酯，总收率36.0%，其结构经过¹H NMR， ¹³C NMR和MS（ESI）确证。     

自组装型紫杉醇键合物前药的合成与性能

以p-氨基苯乙酸(APA)和六亚甲基二异氰酸酯(HDI)为连接基团,将短链聚乙二醇单甲醚(mPEG)键合到紫杉醇(PTX)上,获得双亲型PTX前药mPEG-APA-PTX和mPEG-HDI-PTX.考察了这两种前药在自主装、体外药物释放动力学、体外细胞毒性和体内血浆清除速率等方面的表现.结果表明:两前药均能在水中自组装形成稳定的纳米颗粒,载药量高达28％;mPEG-HDI-PTX纳米颗粒在水溶液中非常稳定,细胞毒性很弱,在血液系统中清除很快,而mPEG-APA-PTX纳米颗粒在pH=7.4的环境下可缓慢释放出原药PTX,细胞毒性与临床用紫杉醇针剂Tax-ol(R)相当,体内循环时间较Taxol(R)明显延长;mPEG-APA-PTX是一种可自组装、载药量高、体内循环时间长的新型纳米前药.     

Synthesis of a Dopamimetic Thionated Dipeptide Prodrug of L-DOPA

L-DOPA has gained widespread credit over the past decades as being the mainstay of the pharmacological treatment of Parkinson‘s disease. However, there are many adverse effects associated with the use of L-DOPA. The prodrug approach is the most promising way to solve the problem. In this article, a thionated dipeptide prodrug of L-DOPA 11 was synthesized via 10 steps in a total yield of 26.5% from L-DOPA.     

Dendrimers as Non-Viral Vectors in Gene-Directed Enzyme Prodrug Therapy

Gene-directed enzyme prodrug therapy (GDEPT) has been intensively studied as a promising new strategy of prodrug delivery, with its main advantages being represented by an enhanced efficacy and a reduced off-target toxicity of the active drug. In recent years, numerous therapeutic systems based on GDEPT strategy have entered clinical trials. In order to deliver the desired gene at a specific site of action, this therapeutic approach uses vectors divided in two major categories, viral vectors and non-viral vectors, with the latter being represented by chemical delivery agents. There is considerable interest in the development of non-viral vectors due to their decreased immunogenicity, higher specificity, ease of synthesis and greater flexibility for subsequent modulations. Dendrimers used as delivery vehicles offer many advantages, such as: nanoscale size, precise molecular weight, increased solubility, high load capacity, high bioavailability and low immunogenicity. The aim of the present work was to provide a comprehensive overview of the recent advances regarding the use of dendrimers as non-viral carriers in the GDEPT therapy.     

TP-CSO: A Triptolide Prodrug for Pancreatic Cancer Treatment

Triptolide (TP) is a potential drug candidate for the treatment of cancer, but its use was hampered by its systemic toxicity and poor water solubility. Hence, a TP-CSO prodrug was synthesized by conjugating TP to chitosan oligosaccharide (CSO), and characterized by ¹H NMR, FTIR, DSC and XRD analyses. The TP-CSO containing about 4 wt% of TP exhibited excellent water solubility (15 mg/mL) compared to TP (0.017 mg/mL). Compared with TP, the pharmacokinetics of the conjugate after oral administration showed a three-fold increase in the half-life in the blood circulation and a 3.2-fold increase in AUC _(0–∞). The orally administered TP-CSO could more effectively inhibit tumor progression but with much lower systemic toxicity compared with TP, indicating significant potential for further clinical trials. In conclusion, CSO-based conjugate systems may be useful as a platform for the oral delivery of other sparingly soluble drugs.     

含葡糖基酮洛芬乙烯醇酯共聚物的合成及其药物释放性能

分别利用化学法和酶促法合成了酮洛芬乙烯酯和葡萄糖丁二酸乙烯酯（6-O-乙烯丁二酰-D-葡萄糖）2种聚合单体,通过2种单体的自由基聚合反应制备了具有较高分子量的酮洛芬葡萄糖共聚物前药,通过IR、NMR对聚合物的结构进行了表征,用GPC方法测定共聚物分子量。 研究了聚合单体投料比例对共聚物分子量和载药量的影响。 结果表明,随着药物乙烯酯在投料中比例的增加,聚合物前药的分子量逐渐下降,聚合物中酮洛芬的载药量逐渐增加。 酮洛芬含糖聚合物前药的体外释放研究表明,酮洛芬的释放时间大大延长,达到了缓释的目的,释药速率随着聚合物前药中葡萄糖含量增加而加快。 聚合物前药的释放动力学模拟结果显示,共聚物释药更符合一级动力学释放模型。     

Direct Real‐Time Monitoring of Prodrug Activation by Chemiluminescence

The majority of theranostic prodrugs reported so far relay information through a fluorogenic response generated upon release of the active chemotherapeutic agent. A chemiluminescence detection mode offers significant advantages over fluorescence, mainly due to the superior signal‐to‐noise ratio of chemiluminescence. Here we report the design and synthesis of the first theranostic prodrug monitored by a chemiluminescence diagnostic mode. As a representative model, we prepared a prodrug from the chemotherapeutic monomethyl auristatin E, which was modified for activation by β‐galactosidase. The activation of the prodrug in the presence of β‐galactosidase is accompanied by emission of a green photon. Light emission intensities, which increase with increasing concentration of the prodrug, were linearly correlated with a decrease in the viability of a human cell line that stably expresses β‐galactosidase. We obtained sharp intravital chemiluminescent images of endogenous enzymatic activity in β‐galactosidase‐overexpressing tumor‐bearing mice. The exceptional sensitivity achieved with the chemiluminescence diagnostic mode should allow the exploitation of theranostic prodrugs for personalized cancer treatment.     

Development of a Tumor‐Specific Photoactivatable Doxorubicin Prodrug

This is a retrospective highlight on the publication by Ibsen and coworkers: Localized In Vivo Activation of a Photoactivatable Doxorubicin Prodrug in Deep Tumor Tissue, which appeared in a preceding issue of Photochem. Photobiol. (2013, 89:698–708). The authors describe the synthesis and properties of a novel doxorubicin (DOX) prodrug, DOX‐PCB, which contains a photocleavable linker group. Systemic administration of the prodrug to a tumor‐bearing animal followed by LED/fiber optic 365 nm light delivery allowed active DOX to be released site specifically in the tumor area. This elegant and timely study provides compelling evidence that photocleavable DOX‐PCB can eliminate many of the toxic side effects of DOX that have plagued clinical use of this highly effective antitumor drug for many years.     

Synthesis,Crystal Structure and Biological Activities of Naproxen-eugenol Ester Prodrug

The prodrug, naproxen-eugenol ester, was synthesized by acyl chloride method with naproxen and eugenol as the raw materials. The structure was identified by proton nuclear magnetic resonance(¹H NMR), mass spectrometry(MS), infrared spectrometry(IR) and X-ray diffraction. The compound was crystallized in the orthorhombic system, space group P2₁2₁2₁ with unit cell dimensions a=0.60563(12) nm,b=1.0234(2) nm, c=3.2654(7) nm, a=90°, b=90°, g=90°, V=2.0240(7) nm³, Z=4. Calculated density 1.235 Mg/m³; absorption coefficient: 0.083 mm^-1; F(000)=800; final R₁=0.0564. The analgesic activity and anti-inflammatory were similar to those of naproxen, and the results of ulcerogenic activity indicate that the prodrug can significantly decrease the irritation after oral administration.     

A Paclitaxel Prodrug Activatable by Irradiation in a Hypoxic Microenvironment

The innate hypoxic microenvironment of most solid tumors has a major influence on tumor growth, invasiveness, and distant metastasis. Here, a hypoxia-activated self-immolative prodrug of paclitaxel (PTX₂-Azo) was synthesized and encapsulated by a peptide copolymer decorated with the photosensitizer chlorin e6 (Ce6) to prepare light-boosted PTX nanoparticle (Ce6/PTX₂-Azo NP). In this nanoparticle, PTX₂-Azo prevents premature drug leakage and realizes specific release in hypoxic tumor microenvironment and the photosensitizer Ce6 not only efficiently generates singlet oxygen under light irradiation but also acts as a positive amplifier to promote the release of PTX. The combination of photodynamic therapy (PDT) and chemotherapy results in excellent antitumor efficacy, demonstrating the great potential for synergistic cancer therapy.     

Light-Activated Monomethyl Auristatin E Prodrug Nanoparticles for Combinational Photo-Chemotherapy of Pancreatic Cancer

Pancreatic cancer is a highly fatal disease that is becoming an increasingly leading cause of cancer-related deaths. In clinic, the most effective approach to treat pancreatic cancers is the combination treatment of several chemotherapeutic drugs, including fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), but this approach is not adequate to manage patients due to their severe toxic side effects. Herein, we proposed light-activated monomethyl auristatin E (MMAE) prodrug nanoparticles for combinational photo-chemotherapy and optimized its applications for pancreatic cancer treatment. The photosensitizer (Ce6) and chemotherapeutic drug (MMAE) were conjugated through caspase-3-specific cleavable peptide (KGDEVD). The resulting CDM efficiently promoted the reactive oxygen species (ROS) under visible light irradiation and thereby induced caspase-3 overexpression in pacreatic cancers, which subsequently released the MMAE from the system. Importantly, MMAE released from CDM further amplified the activation of CDM into MMAE by inducing extensive apoptotic cell death in tumor microenvironment for treatment of tumor cells in deep in the tumor tissues as far visible light cannot reach. In addition, CDM formed prodrug nanoparticles via intermolecular π-π stacking and hydrophobic interactions, allowing durable and reliable treatment by preventing fast leakage from the pancreatic cancers via the lymphatic vessels. The CDM directly (intratumoral) injected into pancreatic cancers in orthotopic models through an invasive approach significantly delayed the tumor progression by combinational photo-chemotherapy with less toxic side effects. This study offers a promising and alternative approach for safe and more effective pancreatic cancer treatment via prodrug nanoparticles that combine photodynamic therapy and chemotherapy.     

Efficient Synthesis of Deuterium-Labelled Ganciclovir-d5 and Its Prodrug Valganciclovir-d5

Russian Journal of General Chemistry - An efficient protocol has been developed for the synthesis of deuterium labeled ganciclovir-d5, a potent anti-cytomegalovirus agent and its prodrug,...     

A Rapid Stability-Indicating HPLC Assay for the Arabinosylcytosine Prodrug,Cyclocytidine

Abstract

Hydrolysis of cyclocytidine in aqueous solutions produced arabinosylcytosine which, in some cases, further reacted to form arabinosyluracil. No other degradation products were detected. A rapid isocratic reverse-phase HPLC assay for all three components in mixtures arising from cyclocytidine hydrolysis was developed. The analysis employs a 4.6 cm column together with a low methanol mobile phase containing 1-heptane sulfonic acid at pH 2.9. The ion-paring of cyclo-C, a cation, was independent of pH. However, ion-paring of arabinosylcytosine was controlled by adjusting the pH to 2.9 which is below its pKa of 4.2. The retention time of neutral arabinosyluracil (pKa = 9.2) was not affected by either the pH or the ion-pairing agent. Its separation was achieved by using a primarily aqueous mobile phase with the minimum methanol required for the other components. The time courses for cyclocytidine and its hydrolysis products were successfully defined under a variety of aqueous conditions.     

普萘洛尔乙烯酯前药的高效液相色谱对映体分离

利用OD-H手性柱对普萘洛尔及其3种氨基取代和3种羟基取代的普萘洛尔二酸乙烯酯(N-酰基、O-酰基普萘洛尔丁二酸乙烯酯、N-酰基、O-酰基普萘洛尔己二酸乙烯酯、N-酰基、O-酰基普萘洛尔癸二酸乙烯酯)进行了对映体分离的研究。考察了流动相正己烷中不同醇类添加剂、二乙胺、不同的流速以及不同底物结构对分离的影响,并初步探讨了手性分离机理。结果表明,普萘洛尔、3种不同链长的氨基取代普萘洛尔二酸乙烯酯、以及羟基取代的普萘洛尔己二酸乙烯酯在实验的条件下能够达到基线分离。     

Monoclonal Antibody-conjugated Polyphosphoester-hyd-DOX Prodrug Nanoparticles for Targeted Chemotherapy of Liver Cancer Cells

In order to overcome the limitation of traditional active nano-therapeutic drugs on tumor targeting efficiency which cannot reach the receptor/target in sufficient amount in the body, in this work, we developed a monoclonal antibody(mAb) and a polymer-hyd-doxorubicin prodrug conjugate, which enables the self-assembled nanoparticles to have precise targeting, tumor tissue aggregation and pH-sensitive drug release. We first prepared an amphiphilic polymer prodrug, abbreviated as H₂N-PEE...