DNA topoisomerase inhibitors

Compiothecc acumiTuua DNA topoisomerase 1 inhibitor, Smith-Kline Beecham product,... 

Nemoto, T, Ojika, M., and Sakagami, Y. (1997) Amphimic adds, novel unsaturated C28 fatty adds as DNA topoisomerase 1 inhibitors from an Australian sponge Amphimedon sp. Tetrahedron Lett., 38, 5667-5670. 

Two ceramide 1-sulfates (9-10) have been obtained from the Japanese bryozoan Watersipora cucullata. These compounds are potent deoxyribonucleic acid (DNA) topoisomerase I inhibitors [37],... 

Ouratea semiserrata Mart (Engl.) (leaves and branches) Biflavones. I-7-O-Methyllanaroflavone (250) 1-7,11-4 -di-O-methyllanaroflavone (251) lanaroflavone (249) amentoflavone (1) podocarpusflavone A (6). Amentoflavone and its aeetyl derivative are inhibitors of human DNA topoisomerases 1 at 200 pM. These biflavonoids showed concentration-dependent growth inhibitory activities on Ehrlich carcinoma cells in 45-h culture. These biflavonoids are targets for DNA topoisomerases and their cytotoxicity is dependent on tumor cell type. Lanaroflavone is an active antiplasmodial compound Velandia et al., 2002[313] Grynber g et al., 2002[48] Weniger et al., 2006[86]. 

Binds irreversibly to the DNA-topoisomerase 1 complex, leading to the irreversible cleavage of DNA and the destruction of cellular topoisomerase 1 by the ubiquitin-proteosome pathway. Induces apopUxsi.s in many normal and tumor cell lines. Potent antimmor agent with anti-inflammatory and antioxidant properties. Potent inhibitor of protein kinase C, EGFR tyrosine kinase, and 1KB kinase. Induces apoptosis of cancer cells. 

No. Topoisomerase 1 inhibitors appear to inhibit initial DNA repairs including sealing of broken strands and repair of base damage following radiation therapy. 

Larsen AK, Grondard L, Couprie J, Desoize B, Comoe L, JardilUer JC, et al. The antileukemic alkaloid fagaronine is an inhibitor of DNA topoisomerases 1 and 11. Biochem Pharmacol 1993 46 1403-12. 

Ataxia telangiectasia mutated (ATM), poly(ADP ribose) polymerase (PARP), DNA-dependent protein kinase, DNA replication factor C, DNA topoisomerase I, DNA fragmentation factor (DFF)45, inhibitor of caspase-activated DNAse (ICAD), lamins A, Bl, and C TRAF-1, Rafl, Ras, GAP, GDP dissociation inhibitor of Rho family GTPases, phospholipase A2, Statl... 

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... 

Topotecan (Hycamtin) [Antineoplasric] WARNING Chemo pre-cautions, for use by healthcare providers familiar w/ chemo agents, BM suppression possible Uses Ovarian CA (cisplatin-reffactory), cervical Ca, NSCLC, sarcoma, ped NSCLC Action Topoisomerase I inhibitor -i- DNA synth Dose 1.5 mg/m2/d as a 1-h IV inf x 5 d, repeat q3wk w/ renal impair Caution [D, -]... 

As reported by Apers et al. [89], podophyllotoxin derivatives can be divided into two groups in terms of their mechanism of action 1 Inhibitors of tubulin polymerization (such as podophyllotoxin), 2 Inhibitors of DNA topoisomerase II (such as etoposide and teniposide). Combining both pharmacophores leads to compounds with a dual mechanism of action, such as azatoxin. 

Some saponins from plants are quite phytotoxic,36 but little is known of their mode(s) of action. Some of these compounds have effects on membrane properties, due to their detergent-like activity. However, all membrane effects are apparently not due to nonspecific effects on membrane lipids. Kauss and Jeblick23 provided indirect evidence that digitonin effects on plant cell Ca2+ uptake are due to effects on membrane protein phosphorylation/dephosphorylation processes. Betulin (Fig. 10.1), a phytotoxic saponin,22 is known for its pharmaceutical activity. It is an inhibitor of DNA topoisomerase.45 The natural product-based DNA topoisomerase inhibitor drug podophyllotoxin is also phytotoxic.37... 

COMPARE analysis can also be used to identify de novo new classes of compounds directed against known targets. For many yearS/ the camptothecin class of compounds was the only explored class of inhibitors of topoisomerase 1, an enzyme responsible for DNA single-strand breaks and religation. COMPARE analysis/ however/ showed a high correlation between camptothecins and a previously unexplored class of compounds known as indenoisoquinolin.es. Confirmatory testing revealed that the hide no isoquinolines did in fact inhibit topoisomerase I (22). 

A Wadsworth-Emmons reaction of the phosphonate (250) with the aldehyde (251) has been used as a key step in a total synthesis of analogues (252) and (253) of topostin B-1, an inhibitor of mammalian DNA topoisomerase The enzyme-catalysed aldol condensation between the phosphonate aldehyde (254) and dihydroxyacetone phosphate is followed by spontaneous intramolecular olefination of the product to give the cyclitol (256) in spite of the reaction being below pH 7 at all times.Attempts at a similar reaction of the homologue (255) were unsuccessful probably because (255) is a poor substrate for the aldolase. 

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