Design, synthesis, and activity evaluation of broad-spectrum small-molecule inhibitors of anti-apoptotic Bcl-2 family proteins: characteristics of broad-spectrum protein binding and its effects on anti-tumor activity.

On the basis of the comparison of the structure of the Bim BH3: Bcl-x(L) complex and that of the ABT-737: Bcl-x(L) complex, a series of class A compounds were designed. These compounds had the basic skeleton of ABT-737 and the h2 residues of Bim BH3. These residues had shown themselves to be relevant to Bim BH3's broad-spectrum binding properties in saturation mutagenesis assays. Unlike ABT-737, which is a selective inhibitor of anti-apoptotic members of the Bcl-2 protein family, the class A compounds showed broad-spectrum binding activity to target proteins similar to those of Bim BH3 peptide. Then class B compounds were synthesized by modifying the structure of the most effective class A compound, A-4. Most of these class B compounds showed better binding affinity to the target proteins than the class A compounds had. They also showed themselves more effective than ABT-737 at inhibiting growth in multiple tumor cell lines known to express Bcl-x(L), Bcl-2, and Mcl-1 proteins at high levels. Compounds B-11 and B-12 had the strongest anti-tumor activity of any compounds we produced. This study suggests that it is feasible to design small-molecule inhibitors based on the structure of Bim BH3, which shows broad-spectrum binding to Bcl-x(L), Bcl-2, and Mcl-1 proteins. Our results also suggest that the broad-spectrum properties of small-molecule inhibitors binding to target proteins play a critical role in inhibiting the growth of many tumor cells. Finally, our study provides a series of lead compounds that merit further research into anti-cancer therapeutics.

[Responses of soil fauna to environment degeneration in the process of wind erosion desertification of Hulunbeir steppe].

To reveal the relationships between soil fauna and soil environmental factors in the process of steppe desertification, field survey combined with laboratory analysis was made to study the community structure, population density and biodiversity of soil fauna, and their relationships with the changes of soil organic matter, hydrolysable nitrogen, available phosphorus and moisture contents and soil pH at different stages of desertification of Hulunbeir steppe. The soil faunal specimens collected belonged to 4 phyla, 6 classes and 12 orders. Nematoda was the only dominant group of medium- and small-sized soil fauna, occupying 94.3% of the total, while Coleoptera and Hemiptera were the dominant groups of large-sized soil fauna, with the amount of 79.7%. The group amount, population density, diversity, and evenness of soil fauna had an obvious decreasing trend with the aggravation of steppe desertification. At serious stage of desertification, soil fauna vanished completely. The population density of soil fauna in 0-20 cm soil layer had significant linear correlations with soil nutrients and moisture contents, soil pH, and litter mass, indicating that soil fauna had stronger sensibility to the changes of soil environmental factors in the process of wind erosion desertification of Hulunbeir steppe.