Solid-phase approach to the synthesis of cyclen scaffolds from cyclotetrapeptides

Cyclen derivatives, as coordinating ligands, have recovered considerable interest for the development of diagnostic and therapeutic drugs, mimicking the binding site of metalloproteins. We demonstrate that the on-resin reduction of head-to-tail cyclotetrapeptides, anchored to a solid support by the side-chain of a trifunctional amino acid, is an efficient synthetic strategy. The proposed approach leads to the cyclen scaffold still bound to the resin, ready for further decorations.     

Polymer-support Selenium-induced Electrophilic Cyclization： Solid-phase Synthesis of Flavonoids

In recent years, the solid-phase synthesis of small heterocyclic molecules has been a subject of intense research activity. Flavonoids are natural products from plants, which have been shown to elicit antitumoral, antiplatelet, antiischemic, antiallergic,…     

甲状旁腺素1-34肽的固相合成

以Wang树脂为固相载体,改进Fmoc(芴甲氧羰基)/tBu法,采用HPLC二次纯化,合成了甲状旁腺素1-34肽,产率23.3%,纯度大于99%(HPLC)。     

新型多肽固相合成链接子{4-[叔丁氧羰基氨基-(2’,4’-二甲氧基苄基)]苯氧基乙酸}的合成

以4-羟基苯甲酸和间苯二甲醚为原料,经傅-克酰基化反应、苄基保护、还原氨化、Boc保护氨基、脱苄基、亲核取代反应、酯水解等7步反应合成了一个新型的多肽固相合成的链接子4-[叔丁氧羰基氨基-(2’,4’-二甲氧基苯基)]苯氧基乙酸,总收率47.2%,纯度>98%,其结构经1H NMR,13C NMR和HR-MS确证。     

经济实用的Boc保护氨基酸键合氯甲基树脂的方法研究

在固相多肽合成中, 探索一种经济有效的Boc保护氨基酸键合氯甲基树脂的方法. 采用K₂CO₃/KI作为键合试剂, 一步合成产物, 反应条件为: Boc保护氨基酸2.5倍量, K₂CO₃ 2.5倍量, KI 0.01倍量, 氯甲基树脂1.0倍量, 普通DMF作反应溶剂, 70 ℃空气浴中旋转反应25 h. 考察了28种不同结构的氨基酸底物在此条件下与氯甲基树脂的键合收率, 大多数氨基酸都能得到几乎定量的酯化产率. 并选取了不同空间位阻的4种Boc保护氨基酸, 比较了KOH, Cs₂CO₃, TEA/KI, DCHA/KI, DIPA/KI, Cs₂CO₃/KI和K₂CO₃/KI等不同键合条件对收率的影响. 结果表明, 除Boc-Asn-OH外, K₂CO₃/KI条件与Cs₂CO₃/KI的效果大体相同, 但K₂CO₃/KI更为经济、可行.     

Facile solid-phase synthesis of head-side chain cyclothiodepsipeptides through a cyclative cleavage from MeDbz-resin

Head to side-chain cyclothiodepsipeptides were conveniently prepared through a cyclative cleavage using the MeDbz linker. Briefly, the peptide sequence was elongated on a MeDbz-Gly-ChemMatrix resin and reacted with 4-nitrophenyl chloroformate, followed by treatment with DIEA to render an activated cyclic N-acyl-N′-methylurea-resin. Removal of the Cys protecting group and further treatment with DIEA allowed the formation of the thiolactone with the concomitant release of the cyclic peptide from the resin.     

Synthesis of Nitrogen-containing Cyclopeptides from N-Terminal Lysine Precursor on Solid Supports

Three synthetic routes for the preparation of nitrogen containing cyclic compounds have been developed, in which the assembling of Fomc-Lys(Boc) residue at N-terminal of resin-bound intermediates is a key prerequisite. Six peptides with nitrogen containing local cyclic structure were efficiently synthesized in good yield starting from chloromethyl resin.     

Synthesis of novel isoindolone derivatives via cascade reactions. Contrasting diastereoselectivity under solution-phase vis-a-vis solvent-free ball-milling reaction conditions

The highly diastereoselective synthesis, crystallographic analysis, and full characterization of several novel heterocycle-fused isoindolones is described. The synthetic strategy involves a cascade Michael/aldol-like cyclization reaction between N-substituted phthalimides rac-1 or 2 and several α,β-unsaturated electrophiles to afford the tricyclic systems pyrrolo[2,1- a]isoindolone and tetrahydropyrido[2,1-a]isoindolone. This synthetic strategy offers a convenient alternative to existing procedures for the preparation of isoindolone derivatives fused to five- and six-membered rings. X-ray crystallographic analysis allowed the determination of relative configurations and revealed that the synthesized compounds exhibit significant structural distortion, especially in the five membered rings. Relevantly, the diastereomeric distribution of products depends substantially on whether the cascade reaction is carried out under solution vis-a-vis solvent-free conditions.     

An Improved Synthesis of Laminin Fragment CR9

Laminin nonapeptide CR9 was synthesized via two different methods.A notably enhanced yicld(46.8%)was obtained from method B compared to that(12.4%)from standard protocol(method A).     

Novel and facile solution-phase synthesis of 2,5-diketopiperazines and O-glycosylated analogs

This work describes the synthesis in solution of a series of related diketopiperazines with potential biological activities: cyclo(l-Pro-l-Ser), cyclo(l-Phe-l-Ser), cyclo(d-Phe-l-Ser) and the corresponding glycosylated analogs of the latter, cyclo[d-Phe-l-Ser(αGlcNAc)] and cyclo[d-Phe-l-Ser(βGlcNAc)]. The synthetic approach involved coupling reactions of -OH or O-glycosylated serine benzyl esters with NFmoc-protected amino acids (Pro or Phe), followed by one-pot deprotection-cyclization reaction in the presence of 20% piperidine in DMF.     

含杂环残基及非经典环化RGD相关肽的合成

以不同的非天然结构代替RGD (Arg-Gly-Asp, 精氨酰甘氨酰天冬氨酸)相关肽中的Arg残基, 共合成了11个改构的RGD相关肽. 其中1～8为杂环残基肽, 9及10为局部杂环肽, 11为主链环肽. 在合成方式上, 产物1～8由传统溶液法制备, 9～11经固相法制备. 全部产物均由MS分析证明结构. 通过本研究, 为探索新型环肽合成提供了有价值的实验基础.     

环六肽Thermoactinoamide A的固相合成及其抗菌活性

采用固相-液相两步法合成一种天然抗菌环肽Thermoactinoamide A。在9-芴甲氧羰基(Fmoc)固相合成的基础上,通过优化N,N-二异丙基乙胺(DIPEA)的添加量,得到直链肽,收率为84%,在此基础上,采用液相环合的方法对直链肽进行环合,通过优化环合体系中混合液的配比、初始pH等条件,得到Thermoactinomide A,收率为51%,总收率43%。抑菌实验结果表明,Thermoactinoamide A对金黄色葡萄球菌的最小抑菌浓度为32μg/m L。固相合成与液相环合两步法合成步骤少、过程简单、产率较高,为进一步研究该天然产物的生物活性及构效关系奠定了基础。     

赖氨酸衍生氮杂大环化合物的固相合成

基于固相载体的假稀释效应, 设计并合成了由赖氨酸为前体结构衍生的氮杂大环化合物8, 9, 10, 12及13. 合成中的关键构件是在固相树脂上肽链的N端键合的二个相邻的赖氨酸残基, 并以溴乙酸为桥连组份, 先后经酰化及亲核取代(S_N2)反应完成三氮杂十六元环骨架的构建. 5种粗产物的总收率在68.9%～86.1%之间, 并全部经氨基酸组成分析及ESI-MS分析表征.     

Merrifield树脂负载的固相法合成1-氨基-2,4-咪唑二酮

设计了两条新的固相有机合成路线合成了1-氨基-2,4-咪唑二酮化合物4. 一条是由Merrifield树脂负载的羟基苯甲醛1a～1c和氨基脲反应得到缩氨基脲树脂2a～2c, 再在乙醇钠存在下和氯乙酸乙酯成环, 经盐酸切割得到1-氨基-2,4-咪唑二酮; 另一条是将Merrifield树脂用二甲基亚砜氧化氯甲基末端醛化后, 与氨基脲反应得到负载的缩氨基脲6, 经环化、切割得到目标产物4. 这两种方法中用1 mol/L的盐酸代替三氟乙酸作为切割剂, 产物单一、操作简便、可定量反应, 是合成1-氨基-2,4-咪唑二酮化合物的新方法.     

A Tripeptide Approach to the Solid-Phase Synthesis of Peptide Thioacids and N-Glycopeptides

A general and robust method for the incorporation of aspartates with a thioacid side chain into peptides has been developed. Pseudoproline tripeptides served as building blocks for the efficient fluorenylmethyloxycarbonyl (Fmoc) solid-phase synthesis of thioacid-containing peptides. These peptides were readily converted to complex N-glycopeptides by using a fast and chemoselective one-pot deprotection/ligation procedure. Furthermore, a novel side reaction that can lead to site-selective peptide cleavage using thioacids (CUT) was discovered and studied in detail.     

Synthesis and Evaluation of Non-Hydrolyzable Phospho-Lysine Peptide Mimics

The intrinsic lability of the phosphoramidate P−N bond in phosphorylated histidine (pHis), arginine (pHis) and lysine (pLys) residues is a significant challenge for the investigation of these post-translational modifications (PTMs), which gained attention rather recently. While stable mimics of pHis and pArg have contributed to study protein substrate interactions or to generate antibodies for enrichment as well as detection, no such analogue has been reported yet for pLys. This work reports the synthesis and evaluation of two pLys mimics, a phosphonate and a phosphate derivative, which can easily be incorporated into peptides using standard fluorenyl-methyloxycarbonyl- (Fmoc-)based solid-phase peptide synthesis (SPPS). In order to compare the biophysical properties of natural pLys with our synthetic mimics, the pK_a values of pLys and analogues were determined in titration experiments applying nuclear magnetic resonance (NMR) spectroscopy in small model peptides. These results were used to compute electrostatic potential (ESP) surfaces obtained after molecular geometry optimization. These findings indicate the potential of the designed non-hydrolyzable, phosphonate-based mimic for pLys in various proteomic approaches.     

Polymer-Supported Synthesis of Various Pteridinones and Pyrimidodiazepinones

In this report, we employed the solid-phase synthetic approach to prepare variously substituted dihydropteridinones, tetrahydropyrrolopteridinones, and pyrimidodiazepinones, using a versatile building block-4,6-dichloro-5-nitropyrimidine. All these compounds are pharmacologically significant scaffolds of the great importance of medicinal chemists. The fast and efficient synthetic methodology is highly desirable for defining their structure-activity relationship (SAR) and optimizing pharmacokinetic properties. Our research efforts utilize simple synthetic methods to generate a library of analogues for future SAR studies. The efficiency of our approach was exemplified in various pteridinones as well as pyrimidodiazepinones.     

基质金属蛋白酶活性中心肽段的合成及纯化

基质金属蛋白酶(MMPs)是一类生物活性依赖于钙锌离子,能降解细胞外基质(extracellar matrix,ECM)的酶家族.目前已发现26个成员,越来越多的研究表明,MMPs在肿瘤侵袭转移中起着重要作用,此作用不仅仅限于它有利于细胞外基质的降解,还对肿瘤微环境的维持和促进肿瘤生长起着重要作用[1].     

反相高效液相色谱/电喷雾质谱法分析化学合成七肽粗产物

利用RP—HPLC／ESI—MS直接分析用芴甲氧羰基(Fmoc)固相多肽合成方法在PHB树脂上偶联合成的一个七肽(H2N—Tyr—Val—Asn-Thr-Asn—Met—Gly—COOH,Mr797．3)粗产物。RP—HPLC显示合成粗产物含有1个主成分,4个次要成分和多个微量成分;与之联用的电喷雾质谱则同步准确地测定出各成分的分子量(m／z)并自动对各主要成分的化学结构进行了串联质谱分析。结果证明,粗产物中的主成分即为目标七肽,另外几个主要副产物为七肽的氧化产物或残缺肽。