蛋白酶体是一种庞大的、多价复合酶，它在承担细胞内蛋白质降解的泛蛋白-蛋白酶体通路（UPP）的关键步骤中起催化作用。UPP不仅可以催化降解异常蛋白质，而且在许多调控蛋白质的更新和加工过程中起重要作用，这些蛋白质的催化过程涉及到人类疾病发病机制的重要生化机制。目前，与UPP有关的酶已被认为是药物设计的分子靶位，蛋白酶体参与调节多种细胞功能，其特异性抑制剂不仅可以作为研究UPP的有利工具，而且也是潜在的抗肿瘤、抗炎药物。本文综述了蛋白酶体抑制剂的药理活性研究进展。

Tat, an essential human immumodeficiency virus type 1 protein interact s with the t ransactivation response element (TAR) and stimulates transcription from the viral long-terminal repeat (LTR). Blockage of Tat-TAR interaction halt sviral transcription and hence replication. In recent years a numbe of studies have suggested various chemicals and/or genetic inhibitors targeting TAR RNA for inhibition of Tatactivated t ranscription. Here, we report these research works.

Replication of HIV-1 requires specific interactions of Tat protein with TAR RNA. Disruption of Tat-TAR RNA interaction could inhibit HIV-1 replication. Here four target compounds were designed and synthesized to bind to TAR RNA for blocking the interaction of Tat-TAR RNA. The core molecule 6,60-diamino-6,60-dideoxy-a,a-trehalose was obtained from selective bromination of, a,a-trehalose at C-6,60, followed by acetylation, azide displacement, deacetylation, and reduction. Coupling of the core molecule with the protected amino acid, then deprotection and guanidinylation generated the novel a,a-trehalose derivatives. Their abilities to inhibit Tat-TAR RNA interaction in human cells were determined by a Tat-dependent HIV-1 LTR-driven CAT assays.

The complex [Mn(L)(NO) (HO)] (1) (L52H-5-hydroxy-1, 2, 5-oxadiazo[3, 4-f]1,10-phenanthroline) was synthesized and character-3222 ized by elemental analysis, IR and UV. The crystal and molecular structure of 1 was determined by single-crystal X-ray diffraction; crystal data: light yellow, monoclinic, space group P2/n, Z54, a 57.432 (2) A, b59.582(3) A, c 523.445(7) A, b 590.519 (5)8. The Mn atom in 11 is hexa-coordinated in a distorted octahedral arrangement by two N atoms of the ligand L and four O atoms of two water molecules and two nitrate anions. Biological tests in vitro showed that 1 has significant antitumor activity against HL-60, KB, Hela and BGC-823 cells. The interaction of 1 with calf thymus DNA was investigated by absorption titration, thermal denaturation and viscosity measurements. The results suggest that 1 binds with DNA by intercalating via the ligand L.

Abstract To study the interactions of these compounds with calf thymus DNA(CT-DNA), seven b-carboline-3-carboxamides were designed and synthesized. The interactions of these compounds with CT-DNA were determined by the viscometric titration assay and Tm (melting temperature) value assay. Binding strengths were evaluated by spectrophotometric titration experiment and microcalorimetric measurement. The interactions of these compounds were tested with CT-DNA. It was showed that all of these compounds were able to change the Tm value of CT-DNA. The results of viscometric titration assay indicated that these compounds interacted with CT-DNA by intercalation. Spectrophotometric titration experiment showed that the binding strengths of these compounds with CT-DNA were different, which was well in agreement with the cell culture results. The binding was driven by entropy according to the results of the microcalorimetric measurement. This series of b-carboline-3-carboxamides is DNA targeting compounds. Their obvious antitumor biological effect is based on the intercalation with DNA base-pairs.

研究了具有抗HIV-1活性的大环多胺类化合物与RNA的识别作用，以及其对cos-7细胞凋亡的影响，以进一步探讨其抗HIV-1的作用机理。实验采用琼脂糖凝胶电泳方法，观察化合物与RNA的识别作用；通过流式细胞计数法探讨其对cos-7细胞凋亡的影响；运用计算机分子模型，从理论上Docking计算化合物与TAR RNA结合的可能性。结果表明，大环多胺类化合物MP-1、MP-2和MP-3不仅具有断裂RNA的作用，并可抑制Tat-RNA的相互作用，还可影响cos-7细胞亚二倍体的含量；理论化学计算数据与实验结果基本一致。这一结果提示化合物的抗HIV-1活性可能通过作用于病毒基因组RNA而发挥作用，是多靶作用的结果。

Synthesis of unimolecularly circular G-quadruplex has been accomplished for the first time during our investigation on the template basis of G-quadruplex through chemical ligations of guanine-rich linear sequencesofoligodeoxyribonucleotides. Theuniqueness of this newly designed circularization course is its self-recognition and self-templating on the scale of individual strand of zligodeoxyribonucleotide in which the same linear sequence serves both as a template and as a substrate simultaneously. The results from our exonuclease and DNAse hydrolysis studies confirm that there is indeed absence of open termini within the structure of the identified circular product. Our subsequent investigation on the loopsize effect indicates that the unimolecularly circular G-uadruplex possessing two or more thymine nucleotides within their connecting loops is readily attainable, while the linear sequence with a single thymine nucleotide between guanine tracts is not a proper precursor for our ligation reaction. In addition, conformation dependency of the circularization course as well as the effects of alkali ions, pH values and concentration of potassium ions on the circularization reaction are examined during our investigation. The implication of our current studies and possible application of the obtained unimolecularly circular G-quadruplex in certain biological processes are also discussed in this report.

The complex [Mn(L)(NO3)2(H2O2)] (1) (L=2H-5-hydroxy-1, 2, 5-oxadiazo[3, 4-f]1,10-phenanthroline) was synthesized and characterized by elemental analysis, IR and UV. The crystal and molecular structure of 1 was determined by single-crystal X-ray diffraction; crystal data: light yellow, monoclinic, space group P21/n, Z=4, a=7.432(2)

整合酶（integrase）对于人免疫缺陷病毒（HIV）-1逆转录病毒的复制来说是必不可少的，因而成为抗艾滋病（AIDS）药物设计的一个理性的靶点。最近文献报道了大量具有抗整合酶活性的化合物，当前最大的挑战就是如何将这些作用于整合酶靶点的先导化合物转变成为临床上有效的抗AIDS药物。

Aseries of bleomycin analogues was prepared with a facile synthetic method. All the compounds were shown to display significant antitumor activity against HeLa and BGC-823 cell lines in vitro. The binding properties with CT-DNAand cleavage efficiency to pBR322 DNAwere investigated, the results indicate that there is a positive relationship between DNAcleavage efficiency and the binding affinity to DNA, and the antitumor activity of the bleomycin analogues is enhanced as the hydrophobicity of the C-terminus substituent side chain increased.