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N-4-羟基苯基维甲酰胺与呋咱氮氧化物偶联物的合成及抗肿瘤活性研究 总被引:3,自引:0,他引:3
为了寻找治疗乳腺癌的药物, 将N-4-羟基苯基维甲酰胺(4-HPR)以乙酸为连接基团通过酯键或酰胺键与NO供体呋咱氮氧化物缀合, 合成了NO供体型维甲酸类化合物, 共11个新的目标化合物, 其结构经IR, MS, 1H NMR和元素分析表征, 总收率为8.8%~12.9%. 对目标物进行体外抗乳腺癌活性测试, 结果表明, 所有目标物均具有不同程度的抗肿瘤活性, 其中8g抗肿瘤活性和对照药阿霉素相当. 相似文献
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靶向抗肿瘤药物甲氨喋呤-琥珀酰壳聚糖缀合物的制备及其体外稳定性的初步探讨 总被引:7,自引:1,他引:6
报道了甲氨喋呤-琥珀酰壳聚糖缀合物的合成方法,并通过紫外光谱、红外光谱及核磁共振谱进行了结构验证.流式细胞仪的检测结果表明,N-琥珀酰壳聚糖对K562白血病肿瘤细胞具有较强的亲和性;溶解性实验结果表明,甲氨喋呤-琥珀酰壳聚糖缀合物的水溶性较好(pH=1~14);体外释放实验结果表明,缀合物性质稳定,能明显延缓甲氨喋呤的释放,为抗肿瘤药物的靶向及缓控释给药体系的研究提供了初步参考. 相似文献
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基于具有三元环状结构的化合物的广泛生理活性和氟尿嘧啶的抗癌作用机制,本文设计、合成并表征了一系列新型5-氟尿嘧啶(5-FU)的三元碳环缀合物及三元氧杂环缀合物。并对5-FU 的N-1和N-3位的选择性烷基化方法进行了系统研究,发现苄氧甲酰氧甲基保护基具有稳定性高、有效保护性好、制备方便、易于脱除等特点,适宜于在本类反应中应用。测试了所合成的新型5-FU三元环缀合物的体外抗肿瘤活性,化合物7、8、12、13显示了对人食管癌细胞Ec9706不同程度的抑制活性。 相似文献
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肾脏缺血缺氧以及再灌注过程都将导致肾小管上皮细胞凋亡,使肾功能严重受损.肾脏的缺血再灌注损伤是移植肾功能延迟恢复的主要原因并能诱导急慢性排斥,影响肾存活率.近年来发现,衍生于促红细胞生成素(EPO)的B螺旋亚基亲水表面序列的肽链(HBSP),对肾脏缺血再灌注损伤具有显著的保护作用,但其在体内极短的半衰期(约2min)极大地限制了它的临床应用.因此,本研究采用构象约束、全D-构型氨基酸替换和N-端封闭策略,设计了3种类型的EPOB螺旋表面肽衍生物,旨在提高其代谢稳定性环肽的设计采用了对氧化还原稳定的硫醚键和相对刚性的亚砜键两种环合方式.在多肽的合成上,采用微波辅助多肽自动合成和手工合成两种模式有机结合;优化了硫醚环合工艺,应用微波加热进行硫醚环肽的合成,大大提高了产率和效率;利用圆二色(CD)谱确定了亚砜环肽的相对构型.活性实验表明,相对于线性母肽HBSP,本文设计合成的代谢稳定衍生肽对大/小鼠肾脏缺血再灌注损伤均有显著提高的保护作用,且硫醚和R-构型亚砜环肽的肾脏保护活性强于S-构型亚砜环肽.而且,环化确实提高了功能肽的血浆稳定性.因此,本文合成的硫醚环肽一周一次注射剂量等效于线性肽HBSP一日三次剂量对小鼠肾损伤的保护作用. 相似文献
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Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers 下载免费PDF全文
Alberto Dal Corso Dr. Michele Caruso Dr. Laura Belvisi Dr. Daniela Arosio Prof. Dr. Umberto Piarulli Dr. Clara Albanese Dr. Fabio Gasparri Dr. Aurelio Marsiglio Dr. Francesco Sola Dr. Sonia Troiani Dr. Barbara Valsasina Dr. Luca Pignataro Dr. Daniele Donati Prof. Dr. Cesare Gennari 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(18):6921-6929
Two small‐molecule–drug conjugates (SMDCs, 6 and 7 ) featuring lysosomally cleavable linkers (namely the Val–Ala and Phe–Lys peptide sequences) were synthesized by conjugation of the αvβ3‐integrin ligand cyclo[DKP–RGD]‐CH2NH2 ( 2 ) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP–RGD]–PTX conjugate with a nonpeptide “uncleavable” linker ( 8 ) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified αVβ3‐integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8 , which possesses a nonpeptide “uncleavable” linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF‐CEM (αVβ3?) and its subclone CCRF‐CEM αVβ3 (αVβ3+). Fairly effective integrin targeting was displayed by the cyclo[DKP–RGD]–Val–Ala–PTX conjugate ( 6 ), which was found to differentially inhibit proliferation in antigen‐positive CCRF‐CEM αVβ3 versus antigen‐negative isogenic CCRF‐CEM cells. The total lack of activity displayed by the “uncleavable” cyclo[DKP–RGD]–PTX conjugate ( 8 ) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload. 相似文献
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Self‐Assembly of Porphyrin–Paclitaxel Conjugates Into Nanomedicines: Enhanced Cytotoxicity due to Endosomal Escape 下载免费PDF全文
Dr. Xiaohua Zheng Dr. Zhensheng Li Prof. Li Chen Prof. Zhigang Xie Prof. Xiabin Jing 《化学:亚洲杂志》2016,11(12):1780-1784
Nanomedicines assembled directly from drug molecules possess several advantages, including precise molecular structure and high content of drugs. Herein, porphyrin–paclitaxel conjugates (Py‐s‐s‐PTX) were synthesized by using a disulfide bond as a linker. The Py‐s‐s‐PTX could self‐assemble into nanoparticles (Py‐s‐s‐PTX NPs) with a size of about 100 nm via disulfide‐induced assembly. Py‐s‐s‐PTX NPs are highly stable under biological conditions and could be destroyed in the presence of reducing agents as revealed by dynamic light scattering. The obtained Py‐s‐s‐PTX NPs could be internalized by cancer cells via endocytosis and disassociated in the reducing cytoplasm, thus releasing PTX in cancer cells. Endosomal escape triggered upon irradiation could enhance the cytotoxicity of paclitaxel, and Py‐s‐s‐PTX NPs possess cytotoxicity comparable to that of free PTX. We believe that this disulfide‐assembled nanomedicine represents a new and important development for chemotherapy in cancer therapy. 相似文献
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Madeeha Shahzad Lodhi Fatima Khalid Muhammad Tahir Khan Zahoor Qadir Samra Shabbir Muhammad Yu-Juan Zhang Kejie Mou 《Molecules (Basel, Switzerland)》2022,27(1)
Therapeutic effects of anticancer medicines can be improved by targeting the specific receptors on cancer cells. Folate receptor (FR) targeting with antibody (Ab) is an effective tool to deliver anticancer drugs to the cancer cell. In this research project, a novel formulation of targeting drug delivery was designed, and its anticancer effects were analyzed. Folic acid-conjugated magnetic nanoparticles (MNPs) were used for the purification of folate receptors through a novel magnetic affinity purification method. Antibodies against the folate receptors and methotrexate (MTX) were developed and characterized with enzyme-linked immunosorbent assay and Western blot. Targeting nanomedicines (MNP-MTX-FR Ab) were synthesized by engineering the MNP with methotrexate and anti-folate receptor antibody (anti-FR Ab). The cytotoxicity of nanomedicines on HeLa cells was analyzed by calculating the % age cell viability. A fluorescent study was performed with HeLa cells and tumor tissue sections to analyze the binding efficacy and intracellular tracking of synthesized nanomedicines. MNP-MTX-FR Ab demonstrated good cytotoxicity along all the nanocomposites, which confirms that the antibody-coated medicine possesses the potential affinity to destroy cancer cells in the targeted drug delivery process. Immunohistochemical approaches and fluorescent study further confirmed their uptake by FRs on the tumor cells’ surface in antibody-mediated endocytosis. The current approach is a useful addition to targeted drug delivery for better management of cancer therapy along with immunotherapy in the future. 相似文献
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Xia Li Min Lu Qi Wu De‐shui Lv Xian‐Fu Lin 《Journal of polymer science. Part A, Polymer chemistry》2008,46(1):117-126
To develop designed polymer–drug conjugates, where the rate of drug liberation and hepatoma cell targeting function could be rationally and widely controlled, we facilely synthesized a series of novel, galactose‐functionalized polymer–acyclovir conjugates with different linkers and first reported the effect of the linker structure including the type of acyclovir‐linked bond (an ester bond or an amide bond) and relative length of the linker between acyclovir and the polymer main chain on release rate and targeting ability of conjugates. In vitro release studies showed that the cumulative released acyclovir from these polymer–acyclovir conjugates was between 24 and 65% in pH 1.2 glycine solution after 7 days. The ester bond more easily underwent hydrolysis than the amide bond. The longer the relative linker length was, the faster the acyclovir was released. The cell recognition experiments visualized using confocal laser scanning microscopy exhibited that the resultant galactose‐functionalized polymer–acyclovir conjugates had evident targeting to hepG2 cells, and targeting ability was also in connection with the relative length of linker. By choosing appropriate linker, cellular internalization of acyclovir could be well achieved. We consider these results to be helpful for the design of multifunctional polymeric prodrugs, in which the required release rate and targeting ability could be rationally controlled by predetermined molecular architecture. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 117–126, 2008 相似文献
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Leva S Lichte A Burmeister J Muhn P Jahnke B Fesser D Erfurth J Burgstaller P Klussmann S 《Chemistry & biology》2002,9(3):351-359
Mirror-image oligonucleotide ligands (Spiegelmers) that bind to the pharmacologically relevant target gonadotropin-releasing hormone I (GnRH) with high affinity and high specificity have been identified using the Spiegelmer technology. GnRH is a decapeptide that plays an important role in mammalian reproduction and sexual maturation and is associated with several benign and malignant diseases. First, aptamers that bind to D-GnRH with dissociation constants of 50-100 nM were isolated out of RNA and DNA libraries. The respective enantiomers of the DNA and RNA aptamers were synthesized, and their binding to L-GnRH was shown. These Spiegelmers bind to L-GnRH with similar affinity to that of the corresponding aptamers that bind to D-GnRH. We further demonstrated dose-dependent inhibition of GnRH-induced Ca(2+) release in Chinese hamster ovary cells that were stably transfected with the human GnRH receptor. 相似文献
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Ginj M Schmitt JS Chen J Waser B Reubi JC de Jong M Schulz S Maecke HR 《Chemistry & biology》2006,13(10):1081-1090
The prototypes for tumor targeting with radiolabeled peptides are derivatives of somatostatin. Usually, they primarily have high affinity for somatostatin receptor subtype 2 (sst2), and they have moderate affinity for sst5. We aimed at developing analogs that recognize different somatostatin receptor subtypes for internal radiotherapy in order to extend the present range of accessible tumors. We synthesized DOTA-octapeptides based on octreotide by replacing Phe3 mainly with unnatural amino acids. The affinity profile was determined by using cell lines transfected with sst1-5. Internalization was determined by using AR42J, HEK-sst3, and HEK-sst5 cell lines, and biodistribution was studied in rat tumor models. Two of the derivatives thus obtained showed an improved binding affinity profile, enhanced internalization into cells expressing sst2 and sst3, respectively, and better tumor:kidney ratios in animals. 相似文献
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Yukio Imanishi Shunsaku Kimura Katsuhiko Yano Shoko Tetsui 《高分子科学杂志,A辑:纯化学与应用化学》2013,50(11):1519-1533
To obtain enchanced and/or unique cellular responses to peptide hormones by simultaneous activation of two different receptor systems, chimera peptide hormones in which enkephalin (EK) is connected through sarcosine oligomer (n) to the message segment of neurotensin [NT(8–13)] were synthesized. Interaction of these two receptor systems was studied by receptor-binding assay and determination of cAMP and cGMP level in cytosol of NG108-15 cells. It was found that EK-12-NT(8- 13) induced specific cell response in terms of the second messenger level. The specific cell response was explained in terms of the enhancement of receptor-receptor interaction in cytosol due to activation of nearby occurring receptors of different kinds. It was also found that EK-12- NT(8-13) has a high affinity toward neurotensin receptor but a low affinity toward enkephalin receptor. To strengthen and prolong the activity of peptide hormones by simultaneous binding with two or more receptors in the target cell, enkephalin/lipid conjugates were immobilized on the surface of polymerized liposomes. It was found that multivalent ligands with a high receptor affinity were synthesized, which was sensibly influenced by the presence of a spacer chain connecting the enkephalin unit to the lipid part. It was found that the introduction of anionic charges to the polymerized liposomes strongly affected the receptor affinity of immobilized ligands. 相似文献
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Self‐Assembly of Amphiphilic Drug–Dye Conjugates into Nanoparticles for Imaging and Chemotherapy 下载免费PDF全文
An amphiphilic drug–dye conjugate ( PTX‐Pt‐BDP ) was designed and synthesized with a platinum compound as the hydrophilic head. The precursor of PTX‐Pt‐BDP was obtained under mild conditions by means of a three‐component Passerini reaction. PTX‐Pt‐BDP could self‐assemble into nanoparticles ( PTX‐Pt‐BDP NPs) in aqueous solution via a nanoprecipitation method. The obtained nanoparticles exhibited favorable structural stability in both water and physiological environment. PTX‐Pt‐BDP NPs could be endocytosed by cancer cells as revealed by confocal laser scanning microscopy and exert potent cytotoxicity. This work highlights the potential of nanomedicines from amphiphilic drug–dye conjugates for cancer cell imaging and chemotherapy. 相似文献
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Lerchen HG Baumgarten J Piel N Kolb-Bachofen V 《Angewandte Chemie (International ed. in English)》1999,38(24):3680-3683
The circumvention of efficient "carbohydrate traps" in the liver is required for targeting glycoconjugates on tumor cells. As shown in the model system of bovine serum albumin (BSA) conjugates, the nature of R(1)-R(3) of the fucose epitope plays an important role in the discrimination of cellular uptake between tumor and liver cells as well as in the cytotoxic activity. 相似文献
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Linares R Pacheco JR Good TA 《Journal of photochemistry and photobiology. B, Biology》2004,77(1-3):17-26
The multichain interleukin-2 receptor (IL-2R) has been proposed as a target for immunotherapy in the treatment of certain cancers including adult T-cell leukemia and cutaneous T-cell lymphoma as well as certain autoimmune diseases. The IL-2R is abnormally expressed on cells associated with each of these diseases; while normal, non-activated T-cells do not express the receptor. This report describes the selective photolysis of activated and non-activated IL-2R expressing cells using several immunoconjugates synthesized with one of two photosensitizers, hematoporphyrin (HP) or chlorin-e(6) (Ce(6)), covalently linked to IL-2 or an anti-IL-2R antibody. Destruction of IL-2R bearing cells was achieved after photosensitizer internalization and irradiation using all tested photosensitizer conjugates. Chlorin containing conjugates were more effective, by a factor of 4 or more, than HP containing conjugates. Conjugates made with IL-2 were up to 30 times more effective than conjugates that used a monoclonal antibody against the IL-2R for targeting. Activation of the cells to increase IL-2R expression decreased the internalization time required for optimal therapeutic efficacy; however, stimulation of the cell to increase IL-2 secretion greatly reduced conjugate effectiveness. This work could lead to the development of more effective strategies to treat T-cell diseases. 相似文献