Synthesis of 2,6-Dimethoxyhydroquinone-3-mercaptoacetyl-peptide-chlorambucil Conjugates

In previous paper, we had reported the synthesis of three conjugates of the cytotoxicity agents: 2,6-Dimethoxyhydroquinone-3-mercaptoacetic acid (DMQ-MA)1, which is a derivative of 2,6-dimethoxy-p-benzoquinone (DMQ). DMQ is a naturally fermented product of wheat germ and was found to have a wide spectrum of cytotoxicity against various tumor cell lines under the synergistic activation of L-ascorbic acid2-5 . Owing to the very low aqueous solubility of DMQ, we prepared derivatives of the …     

Synthesis and DNA Cleavage Studies of 2,6-Dimethoxyhydroquinone-3-Mercaptoacetic Acid Conjugates

In previous paper and work, we reported the synthesis and cytotoxicity studies of a novel series of short chain peptide conjugates of the cytotoxic agent 2, 6-dimethoxyhydro -quinone-3-mercaptoacetic acid1 (DMQ-MA). The DMQ-MA is a derivative of 2,6-dimethoxybenzoquinone, which is a natural product of fermented wheat germ and found to have a wide spectrum of cytotoxicity against various tumor cell lines under the synergistic activation of L-ascorbic acid (AH2)2,3. Compared with DMQ, DMQ…     

Synthesis of Some Novel 2,6- Dimethoxyhydroquinone-3- mercaptoacetyl-peptide Conjugates as Potential Antitumor Agents

2, 6 - D imethoxyhydroquinon e - 3 -mere aptoac et ic ac id (D M Q -MA) I -3 is a syntheti cderivative of 2, 6 - d imethoxyp -b enzoqu inone (D M Q )#, whi oh is a n atUral fermentedproduct of wheat germ and was found to have a wide spectrUm of cytotoxicity againstvarious tUmor cell lines under the synergistic activation of L-ascorbic acid as reported byG.A.Szents. Owing to the very low aqueous solubility of DMQ, which is an apparentdisadvantage for the development as a vaccine, we prep…     

邻苯二甲酰亚胺-多胺缀合物的合成及其生物活性

以邻苯二甲酰亚胺、1,3-丙二胺、1,4-丁二胺为原料,合成了5个邻苯二甲酰亚胺-多胺缀合物．所合成的目标化合物经过^1H NMR、^13C NMR、MS、元素分析确认,并评价了它们对K562（人慢性原白血病细胞）、MB231（乳腺癌细胞）、LnCap（前列腺癌细胞）的生物活性．结果表明：5个目标化合物均不具备抗肿瘤活性,提示多胺衍生化不能提高邻苯二甲酰亚胺的抗肿瘤活性．     

Synthesis and Biological Evaluation of Novel Allobetulon/Allobetulin–Nucleoside Conjugates as AntitumorAgents

Allobetulin is structurally similar tobetulinic acid, inducing the apoptosis of cancer cells with low toxicity. However, both of them exhibited weak antiproliferation against several tumor cell lines. Therefore, the new series of allobetulon/allobetulin–nucleoside conjugates 9a–10i were designed and synthesized for potency improvement. Compounds 9b, 9e, 10a, and 10d showed promising antiproliferative activity toward six tested cell lines, compared to zidovudine, cisplatin, and oxaliplatin based on their antitumor activity results. Among them, compound 10d exhibited much more potent antiproliferative activity against SMMC-7721, HepG2, MNK-45, SW620, and A549 human cancer cell lines than cisplatin and oxaliplatin. In the preliminary study for the mechanism of action, compound 10d induced cell apoptosis and autophagy in SMMC cells, resulting in antiproliferation and G0/G1 cell cycle arrest by regulating protein expression levels of Bax, Bcl-2, and LC3. Consequently, the nucleoside-conjugated allobetulin (10d) evidenced that nucleoside substitution was a viable strategy to improve allobetulin/allobetulon’s antitumor activity based on our present study.     

肽与寡核苷酸缀合物的合成及应用研究进展

寡核苷酸可作为基因表达的抑制剂和潜在的治疗药物,但许多类型的寡核苷酸为聚阴离子化合物,难以跨过细胞膜,而许多生物活性肽具有跨膜与核定位能力,通过合成的方法可以将这两种具有重要功能的生物高聚物以共价键连接在一起,从而实现药物的有效载运．本文综述了肽寡核苷酸缀合物的合成方法及其应用．     

熊果酸半乳糖苷偶联物的合成及保肝活性

通过改进的Koenigs-knorr法在熊果酸3位和28位进行半乳糖苷化得到6个化合物. 通过MTT法考察了上述化合物对大鼠肝干细胞样上皮细胞WB-F344 的作用, 发现化合物12b和12e可明显提高WB-F344细胞的成活率. 体内实验结果表明, 化合物12b, 12d和12f在刀豆蛋白引起的小鼠急性免疫性肝损伤模型上, 除化合物12d对小鼠血清谷草转氨酶升高具有一定程度的降低作用外, 其余化合物均未见对谷草和谷丙转氨酶的升高表现出明显的保护作用.     

Synthesis and Biological Characterization of Monomeric and Tetrameric RGD-Cryptophycin Conjugates

The effective delivery of cytotoxic agents to tumor cells is a key challenge in anticancer therapy. Multivalent integrinspecific ligands are considered a promising tool to increase the binding affinity, selectivity, and internalization efficiency of small-molecule drug conjugates. Herein, we report the synthesis and biological evaluation of a multimeric conjugate containing the high-affinity integrin α_vβ₃ binding ligand RAFT-c(RGDfK)₄, a lysosomally cleavable Val-Cit linker, and cryptophycin-55 glycinate, a potent inhibitor of tubulin polymerization. In vitro cytotoxicity assays verified that the multimeric RGD-cryptophycin conjugate displays improved potency compared to the monomeric analogue in integrin α_vβ₃ overexpressing tumor cell lines, while significantly reduced activity was observed in the integrin-negative cell line.     

位点特异、拓扑结构明确的蛋白质-聚氨基酸偶联物的简洁合成

发展位点特异且具有明确拓扑结构的蛋白质-高分子偶联物是高分子和化学生物学领域共同面对的挑战之一.在聚合物末端精确引入一个或多个具有特殊反应活性的生物正交官能团是实现位点特异生物偶联的关键前提.这一过程通常比较低效、需要多步骤的官能团转化、聚合后修饰以及保护脱保护,费时且繁琐.最近,通过在聚合过程中原位生成官能团,以一锅-两步的过程得到可直接用于蛋白质偶联的异遥爪聚合物,从而实现了多种不同拓扑结构的蛋白质-聚氨基酸偶联物的快速构筑.这一简洁的合成路线实现了以前尚未获得的头-尾相接的环状偶联物的制备,使这些偶联物表现出了很强的体外酶稳定性以及热稳定性.该工作是蛋白质-高分子偶联化学的一次创新的尝试;同时,利用该方法所制备的偶联物在蛋白质药物领域具有广阔的应用前景.     

Progress and Future Directions with Peptide-Drug Conjugates for Targeted Cancer Therapy

We review drug conjugates combining a tumor-selective moiety with a cytotoxic agent as cancer treatments. Currently, antibody-drug conjugates (ADCs) are the most common drug conjugates used clinically as cancer treatments. While providing both efficacy and favorable tolerability, ADCs have limitations due to their size and complexity. Peptides as tumor-targeting carriers in peptide-drug conjugates (PDCs) offer a number of benefits. Melphalan flufenamide (melflufen) is a highly lipophilic PDC that takes a novel approach by utilizing increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside tumor cells. The only other PDC approved currently for clinical use is ¹⁷⁷Lu-dotatate, a targeted form of radiotherapy combining a somatostatin analog with a radionuclide. It is approved as a treatment for gastroenteropancreatic neuroendocrine tumors. Results with other PDCs combining synthetic analogs of natural peptide ligands with cytotoxic agents have been mixed. The field of drug conjugates as drug delivery systems for the treatment of cancer continues to advance with the application of new technologies. Melflufen provides a paradigm for rational PDC design, with a targeted mechanism of action and the potential for deepening responses to treatment, maintaining remissions, and eradicating therapy-resistant stem cells.     

Synthesis of Novel Glucuronide Conjugates of Retinoid Carboxylic Acids

The synthesis and characterization of the novel glucuronide conjugates of 9-cis and 13-cis retinoic acid and of all-trans, 9-cis and 13-cis 4-oxoretinoic acid are described.     

新型双核席夫碱配合物的合成及谱学性质

Eight novel binuclear tetradentate Schiff base complexes (M=Cu(Ⅱ),Ni(Ⅱ),Zn(Ⅱ)) are synthesized. The structure of complexes is two discrete Schiff base unit bridged. The complexes were condensed from series sub-stituent Ketones (5-chloro-2-hydroxybenzophenone, 5-methyl-2-hydroxy-benzophenone, 5-Bromo-2-hydroxybenzop- henone) and dialdehydes (5,5′-methylene-disalicylaldehyde) with the amino group of 1,2-diaminobenzene, and by Metal ion as template. The compounds were characterized by elemental analyses, FT-infrared spectra, Raman, ¹H NMR, UV-vis electronic spectra, EPR spectra. The FT-infrared spectra and Raman spectra of complexes were compared and discussed. The UV-vis election spectra, ¹H NMR and EPR spectra of complexes have also been attributed and minutely analyzed.     

Organic Synthesis and Biological Signal Transduction

The understanding of cellular communication pathways in molecular detail is an important goal of bioorganic research. The synthesis of analogues of active substances (e.g. 1 ) to study the regulation of muscle contraction or the specific lipid modification of representative peptides (→ 2 ) to investigate their subcellular, targeted transfer to intracellular membranes are examples of the capability of organic synthesis is in the research of biological signal transduction mechanisms.     

Expanding the Scope of the Cleavable N-(Methoxy)oxazolidine Linker for the Synthesis of Oligonucleotide Conjugates

Oligonucleotides modified by a 2′-deoxy-2′-(N-methoxyamino) ribonucleotide react readily with aldehydes in slightly acidic conditions to yield the corresponding N-(methoxy)oxazolidine-linked oligonucleotide-conjugates. The reaction is reversible and dynamic in slightly acidic conditions, while the products are virtually stable above pH 7, where the reaction is in a ‘‘switched off-state’’. Small molecular examinations have demonstrated that aldehyde constituents affect the cleavage rate of the N-(methoxy)oxazolidine-linkage. This can be utilized to adjust the stability of this pH-responsive cleavable linker for drug delivery applications. In the present study, Fmoc-β-Ala-H was immobilized to a serine-modified ChemMatrix resin and used for the automated assembly of two peptidealdehydes and one aldehyde-modified peptide nucleic acid (PNA). In addition, a triantennary N-acetyl-d-galactosamine-cluster with a β-Ala-H unit has been synthesized. These aldehydes were conjugated via N-(methoxy)oxazolidine-linkage to therapeutically relevant oligonucleotide phosphorothioates and one DNA-aptamer in 19–47% isolated yields. The cleavage rates of the conjugates were studied in slightly acidic conditions. In addition to the diverse set of conjugates synthesized, these experiments and a comparison to published data demonstrate that the simple conversion of Gly-H to β-Ala-H residue resulted in a faster cleavage of the N-(methoxy)oxazolidine-linker at pH 5, being comparable (T_0.5 ca 7 h) to hydrazone-based structures.     

Synthesis and Cytotoxic Activity of 1,2,4-Triazolo-Linked Bis-Indolyl Conjugates as Dual Inhibitors of Tankyrase and PI3K

A series of new 1,2,4-triazolo-linked bis-indolyl conjugates (15a–r) were prepared by multistep synthesis and evaluated for their cytotoxic activity against various human cancer cell lines. It was observed that they were more susceptible to colon and breast cancer cells. Conjugates 15o (IC₅₀ = 2.04 μM) and 15r (IC₅₀ = 0.85 μM) illustrated promising cytotoxicity compared to 5-fluorouracil (5-FU, IC₅₀ = 5.31 μM) against the HT-29 cell line. Interestingly, 15o and 15r induced cell cycle arrest at the G₀/G₁ phase and disrupted the mitochondrial membrane potential. Moreover, these conjugates led to apoptosis in HT-29 at 2 μM and 1 μM, respectively, and also enhanced the total ROS production as well as the mitochondrial-generated ROS. Immunofluorescence and Western blot assays revealed that these conjugates reduced the expression levels of the PI3K-P85, β-catenin, TAB-182, β-actin, AXIN-2, and NF-κB markers that are involved in the β-catenin pathway of colorectal cancer. The results of the in silico docking studies of 15r and 15o further support their dual inhibitory behaviour against PI3K and tankyrase. Interestingly, the conjugates have adequate ADME-toxicity parameters based on the calculated results of the molecular dynamic simulations, as we found that these inhibitors (15r) influenced the conformational flexibility of the 4OA7 and 3L54 proteins.     

新型大黄酸烟酸偶联物的合成及抗血小板聚集活性

利用拼合原理,以不同碳数的烷烃链为连接臂,将具有活血化瘀作用的大黄酸与降血脂药烟酸偶联,得到相应的新型大黄酸烟酸偶联物(3a~3e),其结构经¹H NMR和HR-MS(ESI)表征。采用比浊法测试了3a~3e的体外抗血小板聚集活性。结果表明：目标化合物均具有一定的体外抗血小板聚集活性。      

蛋白质高分子结合体

蛋白质高分子结合体是蛋白质与高分子化合物以特定位置或方式结合的产物。其中,蛋白质(包括酶和多肽)分子中氨基酸残基上的氨基、巯基和羧基是常用的结合位点。本文主要对蛋白质高分子结合体的制备方法进行了综述。聚乙二醇是合成高分子中能够有效改善蛋白质性能的修饰剂,而多糖则是用于制备蛋白质高分子结合体较成功的天然高分子化合物。“点击化学”、活性聚合技术等技术已经被成功应用于蛋白质高分子结合体的制备。某些具有特异结合功能基团的化合物(如金属卟啉、生物素等)与高分子共价结合后也可制备蛋白质高分子结合体。在研究蛋白质高分子结合体制备方法的基础上,近年来开始了这类大分子的自组装行为研究,尤其是对巨型双亲性分子自组装行为的研究,这为设计和构筑先进功能材料提供了新的思路。与高分子化合物的结合是改善蛋白质性能和拓宽蛋白质应用范围的重要技术之一。蛋白质高分子结合体不但可用于生物医药领域,而且在纳米技术和材料科学等领域具有潜在的优势。