Chromosomes selective inhibition

Introduction 4.1 The basis for selective inhibition of chromosome replication and... 

Clindamycin is a chlorine-substituted derivative of lincomycin. However it is more potent and is better absorbed from the gastrointestinal tract and has therefore replaced lincomycin in most situations. Clindamycin is in principle a bacteriostatic agent. Its indications are mainly limited to mixed anaerobic infections. As mentioned above it has a similar mechanism of action as erythromycin. It selectively inhibits bacterial protein synthesis by binding to the same 50s ribosomal subunits. Erythromycin and clindamycin can interfere with each other by competing for this receptor. Also cross-resistance with erythromycin frequently occurs. Resistance is rather chromosomal rather than plasmid mediated and is especially found in cocci and Clostridium difficile. 

This, of course, limits to some extent the information obtained from hybridization experiments. It should also be pointed out that nuclear D-RNA hybridizes with DNA more effectively than cytoplasmic D-RNA, which indicates that nuclear D-RNA and in particular D-RNA2 is enriched by transcripts from repetitive DNA base sequences (Arion and Georgiev, 1967 Shearer and McCarthy, 1967). Another important fact is that in chromatin the synthesis of RNA on repetitive DNA base sequences is selectively inhibited by chromosomal proteins (Georgiev et al., 1966 Ananieva et al., 1968). 

Monastrol (Figure 10), the most representative Biginelli adduct in anticancer drug development, showed to be a cell permeable molecule whose mechanism of action on cancer cells involves the selective inhibition of kinesin Eg5 [63]. Kinesin Eg5 is a motor enzyme that is responsible for the formation and maintenance of mitotic spindles. The inhibition of this enzyme activity by monastrol leads to the loss of chromosome alignments and bipolar spindle formation. The resulting "monastral phenotype" inspired scientists to name this specific Biginelli compound as monastrol [63]. Fluorastrol (Figure 10), a monastrol-derived Eg5 inhibitor, showed to be more potent... 

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

The five remaining compounds were specifically acting on the mitotic spindle, and did not alter its components in interphase cells. One of them in particular prevented the formation of the spindle in most mitotic cells, replacing it with a monoastral microtubule formation surrounded by chromosomes the compound (9.6, Fig. 9.3) was thus named monastrol. The authors compared monastrol effects with several published effects (21-23) related to inhibition of Eg5, a member of the BimC kinesin family, and showed monastrol to be the a selective Eg5 inhibitor (Eg5-driven microtubule motility inhibition =14 pM). This compound is both the first permeable and selective inhibitor of a specific kinesin, and may have many possible applications as a tool or as the starting point for a chemical optimization program. 

Currently, four benzimidazole compounds are in common use in equine practice fenbendazole, oxibendazole, mebendazole and oxfendazole. The benzimidazoles selectively bind to the nematode p-tubulin and inhibit the formation of microtubules, which are intracellular organelles with a variety of functions including the movement of both energy metabolites and chromosomes during cell division and the provision of the skeletal structure of the cell (Martin 1997). The benzimidazoles essentially starve the nematodes via intestinal cell disruption and inhibit worm egg production. From a clinical standpoint, the most important aspect of the mode of action of the... 

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