新型可注射骨水泥椎弓根螺钉的设计及生物力学研究

目的 探讨一种新型可注射骨水泥椎弓根螺钉(bone cement injectable canulated pedicle screw,CICPS)的设计和生物力学性能,为骨质疏松脊柱疾病的内固定治疗提供一种安全有效的新选择. 方法 (1)在体外、骨质疏松松质骨模型和椎体标本内行骨水泥注射实验,X线片、CT观察骨水泥分布和钉-骨界面情况.(2)取10枚灌注骨水泥后的CICPS和普通椎弓根螺钉行剪切力试验.(3)在松质骨模型中用2～3ml骨水泥强化CICPS行轴向拔出力试验,与普通椎弓根螺钉进行比较. 结果 CICPS各个侧孔均有骨水泥流出,且仅分布于螺钉前部,弥散均匀广泛,未见骨水泥渗漏.CICPS的剪切力为(10600.8±360.1)N,普通螺钉为(15 458.1±311.4)N(P＜0.05).CICPS的最大轴向拔出力为(209.3±13.3)N,普通螺钉为(27.0±5.0)N(P＜0.05).结论 CICPS使骨水泥弥散均匀一致,减少骨水泥渗漏风险,并可显著提高骨质疏松椎体中椎弓根螺钉的把持力.CICPS具有良好的有效性和安全性,为其临床应用提供了理论基础.     

Synthesis and biological activity of potent,low molecular weight renin inhibitors*

A series of renin inhibitors containing the dipeptide transition state mimics (2R, 4S, 5S)-5-amino-4-hydroxy-2-methyl-6-cyclohexyl hexanoic acid (Cha-Ψ[CH(OH)CH₂]Ala) and (2R, 45, 5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexyl hexanoic acid (Cha-Ψ[CH(OH)CH₂]Val) were prepared. A structure-activity study, using pseudopeptide (Boc-Phe-His-Leu-Ψ[CH(OH)CH₂]Val-Ile-His-OH) as our lead structure, led to a new series of inhibitors, which correspond to tripeptides and contain no natural amino acids. For example, R, S-Bpma-Ape-Cha-Ψ[CH(OH)CH₂]Ala-NH₂ (IC₅₀= 1.26 nM against human plasma renin at pH 6.0; molecular weight = 564) has only two thirds of the molecular weight but twice the potency of our original lead. This new class of low molecular weight renin inhibitor displays excellent specificity toward human renin versus the related aspartic proteinase pepsin and angiotensin-1-converting enzyme. Examples are given of selected inhibitors showing encouraging evidence for intestinal absorption after intracolonic and oral administration in male Sprague-Dawley rats.     

甲基丙烯酸羟乙酯-胶原抗菌药物缓释膜促SD大鼠烧伤创面愈合的实验研究

目的考察甲基丙烯酸羟乙酯穴HEMA雪-胶原抗菌药物缓释膜对烧伤创面的促愈合作用。方法制备包裹有磺胺嘧啶银穴SD-Ag雪的HEMA-胶原抗菌药物缓释膜,观察其对SD大鼠深Ⅱ°烧伤模型的作用。63只SD烧伤模型大鼠随机分为3组,A组(21只)以HEMA抗菌药缓释膜治疗,B组(21只)以磺胺嘧啶糊剂治疗,C组(对照组,21只)无治疗。结果实验组大鼠不同时间点的创面愈合率均高于对照组穴P<0.05雪,愈合时间明显缩短穴P<0.05雪。组织学观察可见实验组愈合创面上皮化程度好于对照组。结论HEMA-胶原抗菌药物缓释膜可有效促进大鼠深Ⅱ°烧伤创面愈合,具有一定应用前景。     

Facile degradative lactonization of Gln‐Arg and Gln‐Phe hydroxyethylene dipeptide derivatives*

Abstract: We have found that hydroxyethylene (HE) dipeptide analogs of Gln‐Arg and Gln‐Phe are unusually susceptible to acid catalyzed lactonization. The synthesis of substrate‐based transition state analog inhibitors of botulinum neurotoxin metalloprotease inhibitors that contain the Gln‐Arg or the Gln‐Phe HE units is complicated by this facile degradative lactonization.     

Synthesis of Potent and Orally Active HIV-Protease Inhibitors

A series of potent HIV-protease inhibitors has been prepared. Several of the newly synthesized compounds showed high plasma levels after oral administration to animals. Based on the overall biological profile, CGP 61755 was chosen for further preclinical evaluation. For this compound, a 10 step synthesis potentially suitable for large scale production was developed.     

Interaction of 3′ -O-caffeoyl d-quinic acid with human serum albumin

The interaction of chlorogenic acid (CGA) with human serum albumin (HSA) was studied from the viewpoint of thermodynamics and mechanism of binding at pH 6.0. The association constants (K_a) for the HSA-CGA interaction at 10, 25 and 40° C were 6.0 × 10⁴, 9.0 × 10³ and 2 × 10⁴ M^?1, resulting in AG of -6.21, -5.80, -6.32 kcal/mol, respectively. These high K_a -values showed that the interaction between CGA and HSA is strong, endothermic and entropically driven. Binding of chlorogenic acid induces conformational change in HSA as indicated by quenching of fluorescence emission intensity along with a red shift in the emission maxima from 338 to 350 mm. This suggested the involvement of the lone tryptophan residue in the region of binding. Far-ultraviolet circular dichroic data showed a decrease in the α-helical content of HSA from 56 to 50% upon binding of CGA. These data are also supported by the decrease in the apparent Tm of HSA by 4°C upon binding of CGA causing destabilization of the HSA molecule. The kinetics of the interaction involves a single step in the binding, and the kinetic curve attains equilibrium within 180 ± 5 s. Data on caffeic acid (CA) and quinic acid (QA), which are the hydrolysis products of the bidentate CGA molecule, indicate that CA interacts more strongly than CGA. CA binds with an association constant of 8 × 10⁴ M^?1and with a maximum number of binding sites of four. Microcalorimetric investigation of the interaction of these ligands with HSA suggests that the strength of binding follows the order CA?CGA?>QA with a single class of binding sites. The effect of temperature on the binding of CGA to HSA showed that the interaction is dominated by hydrophobic forces and hydrogen bonding.     

基于羟基亚乙基的β-分泌酶抑制剂的合成

目的深入探讨基于羟基亚乙基二肽的β-分泌酶抑制剂的合成方法。方法综合使用多种有机合成反应来合成拟肽类β-分泌酶抑制剂,包括亲核性加成反应、有机金属试剂协助的取代反应、催化氢化反应、传统多肽偶联反应等。结果以目标化合物之一化合物13作为模型物,通过成功合成化合物13建立了反应条件优化的合成方法。结论本文建立的合成方法可用于构建β-分泌酶抑制剂化学库,发现新的有效化合物。     

Discovery of potent β-secretase （bace-1） inhibitors by the synthesis of isophthalamide-containing hybrids

Aim： The aim of this study was to design and synthesize a series of high activity compounds against aspartyl protease β-secretase （BACE-1） bearing hydroxyethylene （HE） framework. Methods： First, we designed the small library based on our previous work and rational analysis. Subsequently, thirteen compounds were selected and synthesized using skilled solid phase synthetic methods to explore the relationship between structure and activity. We then used molecular modeling to explain the possible binding mode. Results： Thirteen new compounds （6-18） have been designed, synthesized and bioassayed. Their structures were determined by nuclear magnetic resonance （NMR） spectra, low-and high-resolution mass spectra and optical rotation. Most compounds have shown moderate to excellent activities, and compound 10, which contains fewer amino acids and amide bonds than GRL-7234, was about 5-fold more potent than the control compound 4 discovered by Merck. The molecular modeling results have indicated the possible binding mode and explained the difference between compounds 10 and 16, providing direction for further study. Conclusion： This study yielded several high activity compounds bearing fewer amino acids and amide bonds than previous compounds, providing insight into the further development of potent BACE-1 inhibitors for the treatment of Alzheimer＇s disease.     

Potent in vivo inhibitors of rat renin: Analogues of human and rat angiotensinogen sequences containing different classes of pseudodipeptides at the scissile site*

Using solid-phase methodology we have synthesised peptides based on the 8–14 or 6–14 human and rat angiotensinogen sequences, containing the following different isosteric units at the P₁-P₁’cleavage site: Leu-Ψ[CH₂NH]Leu; Leu-[CH(OH)CH₂]Val; Leu-Ψ[CH(OH)CH₂]Leu and Leu-Ψ[CH(NH₂)CH₂]Val. In vitro, peptide Piv-His-Pro-Phe-His-Leu-Ψ[CH(OH)CH₂]Leu-Tyr-Tyr-Ser-NH₂( XXI ) is the most potent inhibitor of rat plasma renin reported having an IC₅₀ of 0.21 nM; it is a much weaker inhibitor of human renin (IC₅₀ 45 nM). Peptide Boc-His-Pro-Phe-His-Leu-Ψ[CH(OH)CH₂] Leu-Val-Ile-His-NH₂ ( XX ) was a highly effective inhibitor of rat renin in vivo. When infused (1 mg/kg/h) into two-kidney, one-clip chronic renal hypertensive rats, it lowered blood pressure and suppressed both plasma renin and angiotensin II. When given as a bolus (1 mg/kg) there was a divergence between the rapid rebound of renin levels and blood pressure, which remained suppressed. These results indicate that potent in vivo inhibitors of rat renin could be useful not only in examining the role of circulating renin but also in elucidating the equally important involvement of extracirculatory renin pools.