Topoisomerase actions

The mechanism of action proposed is based on a direct binding to the channel and the following partial block of the ATP-binding pocket of CFTR (French et al., 1997), a mechanism similar to that used by genistein to inhibit the activity of other ATP-utilizing enzymes such as protein kinases and topoisomerase II (Polkowski and Mazurek, 2000 and refs therein). The selection of flavonoid compounds or the development of synthetic drugs reasonably selective for CFTR activation might be an area for future clinical trials. 

The most important aspect of coralyne is its ability to inhibit DNA relaxation in a fashion significantly similar to the most potent antitumour alkaloid camptothecin, which is known to exert this property [242], Presumably, the most notable biological action of these alkaloids appears to be topoisomerase inhibition [238-242], which has direct relevance to their DNA intercalating property. In this context. Pilch et al. [167] described a mixed binding mode model (Fig. 16) in which the protoberberine structure constitutes portions that can intercalate or bind to the minor groove of DNA. Wang et al. [240] demonstrated that coralyne (Ci) and several of its derivatives (Ce to Ch) (Scheme 5), including the partial saturated... 

The low torsion constant at a = —0.025 is very similar to that observed in a supercoiled pBR322 that was partially relaxed by saturation binding of Escherichia coli single-strand binding (ssb) protein, and which persisted for over a month.(56) It is also similar to that recently inferred from an in vivo assay based on variation in repression efficiency with size of a putative DNA loop.(234) Indeed, it appears that anomalously low torsion constants may be universally encountered in the course of either partial or complete relaxation of supercoiled DNAs, regardless of whether the superhelix density is reduced by action of topoisomerase I, binding of ssb protein, binding of intercalated... 

Neilsen PE (1999) Peptide nucleic acids as therapeutic agents. Curr Opin Struct Biol 9 353-357 Nelson EM, Tewey KM, Liu LF (1984) Mechanism of antitumor drug action poisoning of mammalian DNA topoisomerase II on DNA by 4 -(9-acridinylamino)-methanesulfon-m-anisidide. Proc Natl Acad Sci U S A 81(5) 1361-1365... 

The quinolones are good general antibiotics for systemic infections, and they are particularly useful for urinary tract infections because high concentrations are excreted into the urine. The mode of action involves interference with DNA replication by inhibiting DNA gyrase, a bacterial enzyme related to mammalian topoisomerases that breaks and reseals double-stranded DNA during replication. 

Podophyllotoxin (3) is a precursor to the three cUnically used anticancer drugs, etoposide (4), teniposide (5), and etoposide phosphate (6). Its mechanism of action involves inhibition of tubuUn polymerization and disruption of mitosis during metaphase of the cell cycle. Both etoposide and teniposide are modifications of podophyllotoxin specifically designed to increase the water solubility, reduce gastric toxicity in addition to inhibiting topoisomerase II, and disrupting the cell cycle. 

Etoposide and teniposide are synthetic derivatives of the extract of the American mandragora plant (May Apple). The mechanism of their action has not been completely explained however, they act on the enzyme topoisomerase II, which disturbs the twisting of DNA. In addition, they inhibit DNA and RNA synthesis, as well as transport of nucleotides to cells. Cytotoxic action on normal cells is observed only in very high doses. These drugs exhibit significant activity in lymphomas, leukemia, Kaposi s sarcomas, and in testicular cancer. 

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