Topoisomerase I and

Some are mitosis inhibitors which affect microtubule function and hence the formation of the mitotic spindle, others are topoisomerase I and II inhibitors. 

Quantitative Structure-Activity Reiationships of Heterocyciic Topoisomerase i and ii inhibitors... 

Hansch C, Verma RP (2007) Quantitative Structure-Activity Relationships of Heterocyclic Topoisomerase I and II Inhibitors. 10 43-74 Herncindez-Mateo F, see Santoyo-Gonzdlez F (2007) 7 133-177 Holt H Jr, see Brown T (2006) 2 1-51... 

Hansch and Verma contribute to the quantitative structure-activity relationship (QSAR) analysis of heterocyclic topoisomerase I and II inhibitors. These inhibitors, known to inhibit either enzyme, act as antitumor agents and are currently used in chemotherapy and in clinical trials. 

Makhey D, Gatto B, Chiang Y, Liu A, Liu LF, LaVoie EJ. Coralyne and related compounds as mammalian topoisomerase I and topoisomerase II poisons. Bioorg Med Chem 1996 4 781-791. 

Huang X, Okafuji M, Traganos F, Luther E, Holden E, Darzynkiewicz Z. Assessment of histone H2AX phosphorylation induced by DNA topoisomerase I and II inhibitors topotecan and mitoxantrone and by the DNA cross-linking agent cisplatin. Cytometry A. 2004 Apr 58(2) 99-110. 

Kurose A, Tanaka T, Huang X, Halicka HD, Traganos F, Dai W, Darzynkiewicz Z (2005) Assessment of ATM phosphorylation on Ser-1981 induced by DNA topoisomerase I and II inhibitors in relation to Ser-139-histone H2AX phosphorylation, cell cycle phase, apoptosis. Cytometry A 68(1) 1—9... 

Fig. 4. Nucleosome relaxation, and influence of histone N-terminal tails. Example of nucleosomes on 356 bp ALk= —2.9 topoisomer from the pBR DNA minicircle series [28]. (a) Mononucleosomes (Mo) were reconstituted with control (Control) or acetylated (Acetyl) histones, incubated at 37 °C in Tris buffer [T 50 mM Tris-HCl (pH 7.5), 0.1 mM EDTA, 50 mM KCl, 5 mM MgC, and 0.5 mM dithiothreitol] or phosphate buffer [P same as Tris buffer with 50 mM potassium phosphate (pH 7.5) instead of 50 mM Tris-HCl] in the absence (Topo I —) or presence (Topo I +) of topoisomerase I, and electrophoresed in a native polyacrylamide gel at room temperature. Note the splitting of nucleosome relaxation products in two bands. TE starting chromatin in TE buffer, (b) Gel slices (brackets) were cut out, and eluted DNAs were electrophoresed in a chloroquine-containing native polyacrylamide gel, together with control naked topoisomers (C1-C4). Lanes were numbered as in the (a) gel. Autoradiograms are shown, (c) Radioactivity profiles of lanes 2 and 5 in the (b) gel. Topoisomers are indicated by their ALk values. (Adapted from Fig. 2 in Ref. [28].)...

Saavedra, R.A. and Huberman, J.A. (1986) Both DNA topoisomerases I and II relax 2 micron plasmid DNA in living yeast cells. Cell 45, 65-70. 

Epipodophyllotoxin (122) Alkaloid Tafluposide (123) Oncology Topoisomerase I and II inhibitor Phase I Pierre Fabre 727-729... 

Lavergne O, Harnett J, Holland A, Lanco C, Lesueur-Ginot L, Demarquay D, Huchet M, Coulomb H, Bigg DC. (1999) BN 80927 A novel homo-camptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett 9 2599-2602. 

Barret JM, Kmczynski A, Etievant C, Hill BT. (2002) Synergistic effects of F 11782, a novel dual inhibitor of topoisomerases I and II, in combination with other anticancer agents. Cancer Chemother Pharmacol 49 479 86. 

Cragg CM, Newman DJ, A tale of two tumor targets Topoisomerase I and tubulin. The Wall and Wani contribution to cancer chemotherapy, J Nat Prod 67 232-244, 2004. 

Topoisomerase I and II Glunosy cnramide Synlha e Thynridjtale Synthase Dihydrofotale Reductase Ribonucioolide Reductase Aspartate Transcarbamylase S AdenosylnrY6thionine Synlhase... 

Solary E, Bertrand R, Kohn KW, Pommier Y (1993) Differential induction of apoptosis in imdifferentiated and differentiated HL-60 cells by DNA topoisomerase I and II inhibitors. Blood 81 1359-1368... 

In 1991, Kojiri et al. reported the isolation of BE-13793C (344), an alkaloid isomeric with the arcyriaflavins C (347) and D (348) (see Scheme 2.89), from the culture broth of Streptoverticillium moharaense strain BA 13793 collected in Seto, Aichi Perfecture, Japan. BE-13793C (344) showed strong inhibitory activity against topoisomerases I and II and inhibited the growth of doxorubicin-resistant or vincristine-resistant P-388 murine leukemia cell lines, as well as their parent P-388 cell line (330). 

Extensive structure modulations were performed to obtain more potent and less toxic anti-cancer agents, such as etoposide used in the therapy of numerous cancers (Fig. 41) [113], In contrast to podophyllotoxin, etoposide derivatives act as DNA topoisomerase II inhibitors. Tafluposide (F 11782) is an etoposide where both hydroxyl functions of the glycoside moiety are acylated with the pen-tafluorophenoxyacetic acid (Fig. 41). It has been demonstrated that tafiuposide does not act as a pro-drug of etoposide, but through a specific mechanism of interaction with both topoisomerases I and lla [114]. 

The (3-triketone (17) was isolated from the fermentation broth of an isolate of the bacterium Apiosordaria effusa. The structure of 17 was determined from NMR spectral studies [38]. If the broth was acid treated prior to extraction, a mixture of the two isomers, a- and (3-apiodionen (18, 19) were isolated and were found to be in equilibrium in solution [39]. The absolute stereochemistry of these compounds has not been assigned. Apiodionen exhibited weak activity as inhibitor of topoisomerase I and II [40]. 

Eukaryotic cells also have type I and type II topoisomerases. The type I enzymes are topoisomerases I and III the type II enzymes are topoisomerases Ha and II/3. The eukaryotic type II topoisomerases cannot underwind DNA (introduce negative supercoils), but they can relax both positive and negative supercoils. We consider one probable origin of negative supercoils in eukaryotic cells in our discussion of chromatin in Section 24.3. The process catalyzed by eukaryotic type II topoisomerases is illustrated in Figure 24-22. 

Topoisomerase Interactive Drugs. Topoisomerases I and II have emerged as interesting targets for the design of new anticancer agents (Table 4),... 

Moreau P, Gaillard N, Marminon C, Anizon F, Dias N, Baldeyrou B, Bailly C, Pierre A, Hickman J, Pfeiffer B, Renard P, Prudhomme M (2003) Semi-Synthesis, Topoisomerase I and Kinase Inhibitory Properties, and Antiproliferative Activities of New Rebeccamycin Derivatives. Bioorg Med Chem 11 4871... 

Genistein has been considered the primary anticancer constituent in soy, based on putative in vitro activities that include its ability to inhibit topoisomerase I and II activity, inhibit protein tyrosine phosphorylation, induce differentiation of cancer cell lines, and act as an estrogen agonist. 

Quantitative Structure-Activity Relationships of Heterocyclic Topoisomerase I and II Inhibitors... 

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