Topoisomerase inhibitory

D. indicus Gaertn. is known to abound with anthraquinones, but its pharmacological potential remains unexplored to date (20,21). Note that damnacanthal is a common component of the Damnacanthus species. Faltynek et al. made the interesting observation that damnacanthal inhibits the enzymatic activity of tyrosine kinase, which is involved in the propagation of metastases (22). An interesting development from this observation would be to assess the topoisomerase inhibitory activity of the Damnacan-thus species, an activity that could be associated with tyrosine kinase inhibition, hence enormous chemotherapeutic potentials. 

Wada S, Iida A, Tanaka R. Screening of triterpenoids isolated from Phyllanthus flexuo-sms for DNA topoisomerase inhibitory activity. J Nat Prod 2001 64 1545-1547. 

Esteves-Souza A, Pissinate K, Graja Nascimento Md et al (2006) Synthesis, cytotoxicity, and DNA-topoisomerase inhibitory activity of new asymmetric ureas and thioureas. Bioorg Med Chem 14(2) 492 199... 

Momin, R.A. and Nair, M.G. (2002) Antioxidant, cyclooxygenase and topoisomerase inhibitory compounds from Apium graveolens Linn. Seeds. Phytomedicine 9(4), 312-31 8. 

The mechanism of actions involves tubulin binding, reverse transcriptase inhibition, integrase inhibition and topoisomerase inhibition. Podophyllo-toxins bind to tubulin and are able to disrupt the cellular cytoskeleton and interfere with some vital virus processes. There is no relationship between the inhibition of reverse transcriptase (RT) and chemical structure in the case of lignans, because all the chemical antiviral structures are able to bind to the enzyme. As to the rest of the mechanism, there is not much information available. The effects of rabdosiin may be due to its topoisomerase inhibitory effects. Charlton concluded that the antiviral activity of lignans is not strong and that except for podophyllotoxin, which is used topically to treat various warts caused by HPV, none of them are of interest for commercial application. 

The anticancer potential of lunasin and soy hydrolyzates studied on leukemia cells (Wang de Mejia, 2007) showed that lunasin-enriched soy flour caused cytotoxicity of leukemia cells. Simulated gastrointestinal hydrolysis of soy protein increased topoisomerase inhibitory activities and cytotoxicity. Such hydrolysates contain hydrophilic, small bioactive peptides (<3 kDa), and three novel topoisomerase inhibitory soy peptides that can be isolated. 

Kelm and Nair detected the presence of parthenolide in the hexane extract of M. salicifolia fruits by HPLC [11]. Parthenolide (1) and a related compound, costunolide (2), had shown topoisomerase I (top-l) inhibitory activity (refer to Bioassay Procedures section, Topoisomerase inhibitory bioassays) against Saccharomyces cerevisiae mutant strains hypersensitive to top- poisons [12] (Table 1). The isolation of parthenolide from M. grandiflora [13, 14, 15] and M sieboldii spp. japonica and M. praecoissima a.r. praecoissima [16] is discussed in other studies as well. Costunolide was isolated from the trunk and root bark ether extracts of M sieboldii [17, 18]. Also, parthenolide and costunolide, were isolated from Tanacetum parthenium Asteraceae [19]. The extraction of these compounds by supercritical CO2 (SFCO2) and near critical propane from M. grandiflora has also been carried out [20]. 

Table 1. Topoisomerase Inhibitory Activity of Parthenolide (I), Costunolide (2), Camptothecin, and Etoposide [12]...

Esteves-Souza, A. Pissinate, K. Nascimento, M.G. Grynberg, N.F. Echevarria, A. Synthesis, Cytotoxicity, and DNA-Topoisomerase Inhibitory Activity of New Asymmetric Ureas and Thioureas. Bioorg. Med. Chem. 2006,14,492-499. 

MARKOVITS J, LINASSIER C, FOSSE P, COUPRIE J, PIERRE J, JACQUEMIN-SABLON A, SAUCIER J M, LE PECQ J B, LARSEN A K (1989) Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res. 49 5111-17. 

The plant is known to contain chelerythrine chloride, which inhibits the aggregation of rabbit platelet in vitro via inhibition on thromboxane formation and phosphoinosi-tides breakdown (30). Chelerythrine, which occurs in members of the family Papaver-aceae, has been reported to inhibit the enzymatic activity of protein kinase C and to exert cell-growth inhibitory effect via the induction of apoptosis in numerous cancer cell lines (31,32). What is the topoisomerase activity of chelerythrine ... 

Kampa et al. made the interesting observation that protocatechuic acid, which is found in grapes and red wine from Vitis vimfera (Vitaceae), showed a time- and dose-dependent inhibitory effect on cell growth of T47D human breast cancer cells at low concentrations (108). The phenolic compound is a potent inhibitor of topoisomerase I (109). The plant likely contains some germanacrolides because these sesquiterpenes are known... 

Tosa H, Iinuma M, Asai F, et al. Anthraquinones from Neonauclea calycina and their inhibitory activity against DNA topoisomerase II. Biol Pharm Bull 1998 21 641-642. 

Wada S, Reiko T, Akira I, Shunyo M. In vitro inhibitory effects of DNA topoisomerase II by femane-type triterpenoids isolated from a Euphorbia genus. Bioorg Med Chem Lett 1998 8 2829-2832. 

The fungal metabolites TAN-1496 A, C, and E (isolated from the culture broth of Microsphaeropsis sp. FL-16144) have been shown to have specific inhibitory activity against DNA topoisomerase 1. DNA topoisomerase 1 is an enzyme responsible for DNA metabolism and have been proposed as an intracellular target for cancer chemotherapy. ... 

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. 

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). 

Irinotecan is a topoisomerase-I inhibitory agent that prevents the initiation and elongation of RNA transcription, DNA replication, and supercoiling of DNA (44). Investi-... 

Thiazole-containing linear peptides have also been isolated from tunicates. Virenamides A-E (412-416) were obtained from the didemnid tunicate Diplosoma virens, which contains symbiotic prokaryotic algae in its cloacal cavity. The structures of virenamides A-C were determined by HPLC analysis using Marfey s procedure [323] while the absolute stereochemistry of virenamide E (416) was proven by its synthesis from virenamide A (412) [324], Compounds 412-416 showed modest cytotoxicity toward a panel of cultured cells and 412 also exhibited topoisomerase II inhibitory activity. 

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... 

Czuwara-Ladykowska J, Makiela B, Smith EA, Trojanowska M, Rudnicka L. The inhibitory effects of camptothecin, a topoisomerase I inhibitor, on collagen synthesis in fibroblasts from patients with systemic sclerosis. Arthritis Research 2001, 3,311-318. 

Optically active pipecolic acid and its derivatives can be prepared via 4-phenylpyrido[2,l-c][l,4]oxazin-l-one derivatives. Representatives of the third generation of quinoline-3-carboxylic acid antibacterial agents ofloxacin (19), its levorotatory enantiomer, levofloxacin (20), and rufloxacin (21) have gained wide acceptance for the treatment of bacterial infections of the respiratory and urinary tracts, skin, and soft tissues, as well as sexually transmitted diseases, and pazufloxacin (22) is under development. Other 10-aryl-9-fluoro-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-de]-l,4-benzox-azine-6-carboxylic acids and 7//-pyrido[l,2,3-de]-l,4-benzothiazine-6-carboxylic acids exhibit mammalian topoisomerase II inhibitory activity. 

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