مهارکننده‌های توپوایزومراز(به انگلیسی: Topoisomerase inhibitor) ترکیبات شیمیایی هستند که عملکرد توپوایزومرازها را مسدود می‌کنند (توپوایزومراز I و II)، آنزیم‌هایی هستند که تغییرات در ساختار DNA را با کاتالیز فرایند شکستن و اتصال مجدد ساختار فسفودی‌استر رشته‌های DNA در چرخه سلولی عادی، کنترل می‌کنند.
در سال‌های اخیر، توپوایزومرازها به عنوان هدف در شیمی درمانی سرطان مورد توجه قرا گرفته‌اند. تصور می‌شود که مهارکننده‌های توپوایزومراز مرحله لیگاز شدن چرخه سلولی را مسدود می‌کنند و باعث ایجاد وقفه‌های تک و دو رشته‌ای می‌شوند که به یکپارچگی ژنوم آسیب می‌رسانند. این وقفه‌ها، متعاقباً منجر به آپوپتوز و مرگ سلولی می‌شود.
مهارکننده‌های توپوایزومراز همچنین می‌توانند به عنوان عوامل ضد باکتری عمل کنند.کوینولون‌ها (از جمله اسید نالیدکسیک و سیپروفلوکساسین) این عملکرد را دارند.
کتابشناسی
- Antony S, Agama KK, Miao ZH, Takagi K, Wright MH, Robles AI, Varticovski L, Nagarajan M, Morrell A, Cushman M, Pommier Y (Nov 2007). "Novel indenoisoquinolines NSC 725776 and NSC 724998 produce persistent topoisomerase I cleavage complexes and overcome multidrug resistance". Cancer Res. 67 (21): 10397–405. doi:10.1158/0008-5472.can-07-0938. PMID 17974983.
- Antony S, Agama KK, Miao ZH, Hollingshead M, Holbeck SL, Wright MH, Varticovski L, Nagarajan M, Morrell A, Cushman M, Pommier Y (2006). "Bisindenoisoquinoline bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA intercalator and topoisomerase inhibitor with antitumor activity". Mol. Pharmacol. 70 (3): 1109–1120. doi:10.1124/mol.106.024372. PMID 16798938.
- Antony S, Kohlhagen G, Agama K, Jayaraman M, Cao S, Durrani FA, Rustum YM, Cushman M, Pommier Y (Feb 2005). "Cellular topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison". Mol. Pharmacol. 67 (2): 523–30. doi:10.1124/mol.104.003889. PMID 15531731.
- Antony S, Jayaraman M, Laco G, Kohlhagen G, Kohn KW, Cushman M, Pommier Y (Nov 2003). "Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I.". Cancer Res. 63 (21): 7428–35. PMID 14612542.
- Bakshi RP, Sang D, Morrell A, Cushman M, Shapiro TA (Jan 2009). "Activity of indenoisoquinolines against African trypanosomes". Antimicrob. Agents Chemother. 53 (1): 123–8. doi:10.1128/aac.00650-07. PMC 2612167. PMID 18824603.
- Baxter J, Diffley JF (Jun 2008). "Topoisomerase II inactivation prevents the completion of DNA replication in budding yeast". Molecular Cell. 30 (6): 790–802. doi:10.1016/j.molcel.2008.04.019. PMID 18570880.
- Burgess DJ, Doles J, Zender L, Xue W, Ma B, McCombie WR, Hannon GJ, Lowe SW, Hemann MT (Jul 2008). "Topoisomerase levels determine chemotherapy response in vitro and in vivo". Proc. Natl. Acad. Sci. USA. 105 (26): 9053–8. Bibcode:2008PNAS..105.9053B. doi:10.1073/pnas.0803513105. PMC 2435590. PMID 18574145.
- Cho WJ, Le QM, My Van HT, Youl Lee K, Kang BY, Lee ES, Lee SK, Kwon Y (Jul 2007). "Design, docking, and synthesis of novel indeno[1,2-c]isoquinolines for the development of antitumor agents as topoisomerase I inhibitors". Bioorg. Med. Chem. Lett. 17 (13): 3531–4. doi:10.1016/j.bmcl.2007.04.064. PMID 17498951.
- Cinelli MA, Cordero B, Dexheimer TS, Pommier Y, Cushman M (Oct 2009). "Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: investigating the hypothesis of shared structure-activity relationships". Bioorg. Med. Chem. 17 (20): 7145–55. doi:10.1016/j.bmc.2009.08.066. PMC 2769207. PMID 19783447.
- Cinelli MA, Morrell AE, Dexheimer TS, Agama K, Agrawal S, Pommier Y, Cushman M (Aug 2010). "The structure-activity relationships of A-ring-substituted aromathecin topoisomerase I inhibitors strongly support a camptothecin-like binding mode". Bioorg. Med. Chem. 18 (15): 5535–52. doi:10.1016/j.bmc.2010.06.040. PMC 2911012. PMID 20630766.
- Cinelli MA, Morrell A, Dexheimer TS, Scher ES, Pommier Y, Cushman C (Aug 2008). "Design, synthesis, and biological evaluation of 14-substituted aromathecins as Topoisomerase I inhibitors". J. Med. Chem. 51 (15): 4609–19. doi:10.1021/jm800259e. PMC 2538619. PMID 18630891.
- Cushman M, Jayaraman M, Vroman JA, Fukunaga AK, Fox BM, Kohlhagen G, Strumberg D, Pommier Y (Oct 2000). "Synthesis of new indeno[1,2-c]isoquinolines: cytotoxic non-camptothecin topoisomerase I inhibitors". J. Med. Chem. 43 (20): 3688–98. doi:10.1021/jm000029d. PMID 11020283.
- Holleran JL, Parise RA, Yellow-Duke AE, Egorin MJ, Eiseman JL, Covey JM, Beumer JH (Sep 2010). "Liquid chromatography-tandem mass spectrometric assay for the quantitation in human plasma of the novel indenoisoquinoline topoisomerase I inhibitors, NSC 743400 and NSC 725776". J. Pharm. Biomed. Anal. 52 (5): 714–20. doi:10.1016/j.jpba.2010.02.020. PMC 2865235. PMID 20236781.
- Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M (2005). "Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis". J. Med. Chem. 48 (15): 4803–14. doi:10.1021/jm050076b. PMID 16033260.
- Kinders RJ, Hollingshead M, Lawrence S, Ji J, Tabb B, Bonner WM, Pommier Y, Rubinstein L, Evrard YA, Parchment RE, Tomaszewski J, Doroshow JH (Nov 2010). "Development of a validated immunofluorescence assay for yH2AX as a pharmacodynamic marker of topoisomerase I inhibitor activity". Clin. Cancer Res. 16 (22): 5447–57. doi:10.1158/1078-0432.ccr-09-3076. PMC 2982895. PMID 20924131.
- Kiselev E, Dexheimer TS, Pommier Y, Cushman M (Dec 2010). "Design, synthesis, and evaluation of dibenzo[c,h][1,6]naphthyridines as topoisomerase I inhibitors and potential anticancer agents". J. Med. Chem. 53 (24): 8716–26. doi:10.1021/jm101048k. PMC 3064471. PMID 21090809.
- Marchand C, Antony S, Kohn KW, Cushman M, Ioanoviciu A, Staker BL, Burgin AB, Stewart L, Pommier Y (Feb 2006). "A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trappingof topoisomerase I-DNA covalent complexes". Mol. Cancer Ther. 5 (2): 287–95. doi:10.1158/1535-7163.mct-05-0456. PMC 2860177. PMID 16505102.
- Morrell A, Placzek M, Parmley S, Grella B, Antony S, Pommier Y, Cushman M (Sep 2007). "Optimization of the indenone ring of indenoisoquinoline topoisomerase I inhibitors". J. Med. Chem. 50 (18): 4388–404. doi:10.1021/jm070307+. PMID 17676830.
- Morrell A, Placzek M, Parmley S, Antony S, Dexheimer TS, Pommier Y, Cushman M (Sep 2007). "Nitrated indenoisoquinolines as topoisomerase I inhibitors: a systematic study and optimization". J. Med. Chem. 50 (18): 4419–30. doi:10.1021/jm070361q. PMID 17696418.
- Morrell A, Jayaraman M, Nagarajan M, Fox BM, Meckley MR, Ioanoviciu A, Pommier Y, Antony S, Hollingshead M, Cushman M (Aug 2006). "Evaluation of indenoisoquinoline topoisomerase I inhibitors usinga hollow fiber assay". Bioorg. Med. Chem. Lett. 16 (16): 4395–9. doi:10.1016/j.bmcl.2006.05.048.
- Nagarajan M, Morrell A, Antony S, Kohlhagen G, Agama K, Pommier Y, Ragazzon PA, Garbett NC, Chaires JB, Hollingshead M, Cushman M (Aug 2006). "Synthesis and biological evaluation of bisindenoisoquinolines as topoisomerase I inhibitors". J. Med. Chem. 49 (17): 5129–40. doi:10.1021/jm060046o.
- Nagarajan M, Xiao X, Antony S, Kohlhagen G, Pommier Y, Cushman M (2003). "Design, synthesis, and biological evaluation of indenoisoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen". J. Med. Chem. 46 (26): 5712–24. doi:10.1021/jm030313f. PMID 14667224.
- Pfister TD, Reinhold WC, Agama K, Gupta S, Khin SA, Kinders RJ, Parchment RE, Tomaszewski JE, Doroshow JH, Pommier Y (Jul 2009). "Topoisomerase I levels in the NCI-60 cancer cell line panel determined by validated ELISA and microarray analysis and correlation with indenoisoquinoline sensitivity". Mol. Cancer Ther. 8 (7): 1878–84. doi:10.1158/1535-7163.mct-09-0016. PMC 2728499.
- Pommier Y, Cushman M (May 2009). "The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives". Mol. Cancer Ther. 8 (5): 1008–14. doi:10.1158/1535-7163.mct-08-0706.
- Pommier Y, Leo E, Zhang H, Marchand C (May 2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs". Chem. Biol. 17 (5): 421–33. doi:10.1016/j.chembiol.2010.04.012. PMID 20534341.
- Pommier Y (Jul 2009). "DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition". Chem. Rev. 109 (7): 2894–902. doi:10.1021/cr900097c. PMC 2707511. PMID 19476377.
- Pommier Y (2006). "Topoisomerase I inhibitors: camptothecins and beyond". Nat. Rev. Cancer. 6 (10): 789–802. doi:10.1038/nrc1977. PMID 16990856.
- Pommier Y (2004). "Camptothecins and topoisomerase I: a foot in the door. Targeting the genome beyond topoisomerase I with camptothecins and novel anticancer drugs: importance of DNA replication, repair and cell cycle checkpoints". Curr. Med. Chem. Anti-Cancer Agents. 4 (5): 429–34. doi:10.2174/1568011043352777. PMID 15379698.
- Song Y, Shao Z, Dexheimer TS, Scher ES, Pommier Y, Cushman M (Mar 2010). "Structure-based design, synthesis, and biological studies of new anticancer norindenoisoquinoline topoisomerase I inhibitors". J. Med. Chem. 53 (5): 1979–89. doi:10.1021/jm901649x. PMC 2838169. PMID 20155916.
- Sordet O, Goldman A, Redon C, Solier S, Rao VA, Pommier Y (Aug 2008). "Topoisomerase I requirement for death receptor-induced apoptotic nuclear fission". J. Biol. Chem. 283 (34): 23200–8. doi:10.1074/jbc.m801146200. PMC 2516995. PMID 18556653.
- Staker BL, Feese MD, Cushman M, Pommier Y, Zembower D, Stewart L, Burgin AB (Apr 2005). "Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex". J. Med. Chem. 48 (7): 2336–45. doi:10.1021/jm049146p. PMID 15801827.
- Teicher BA (2008). "Next generation topoisomerase I inhibitors: rationale and biomarker strategies". Biochem. Pharmacol. 75 (6): 1262–71. doi:10.1016/j.bcp.2007.10.016. PMID 18061144.
- Seng CH, Chen YL, Lu PJ, Yang CN, Tzeng CC (2008). "Synthesis and antiproliferative evaluation of certain indeno[1,2-c]quinoline derivatives". Bioorg. Med. Chem. 16 (6): 3153–62. doi:10.1016/j.bmc.2007.12.028. PMID 18180162.
- Tuduri S, Crabbé L, Conti C, Tourrière H, Holtgreve-Grez H, Jauch A, Pantesco V, DeVos J, Thomas A, Theillet C, Pommier Y, Tazi J, Coquelle A, Pasero P (Nov 2009). "Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription". Nat. Cell Biol. 11 (11): 1315–24. doi:10.1038/ncb1984. PMC 2912930. PMID 19838172.
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Van HT, Le QM, Lee KY, Lee ES, Kwon Y, Kim TS, Le TN, Lee SH, Cho WJ (Nov 2007). "Convenient synthesis of indeno[1,2-c]isoquinolines as constrained forms of 3-arylisoquinolines and docking study of a topoisomerase I inhibitor into DNA-topoisomerase I complex". Bioorg Med Chem Lett. 17 (21): 5763–7. doi:10.1016/j.bmcl.2007.08.062. PMID 17827007.
{{cite journal}}: نگهداری یادکرد:نام‌های متعدد:فهرست نویسندگان (link) - Nagarajan M.; Morrell A.; Ioanoviciu A.; Antony S.; Kohlhagen G.; Hollingshead M.; Pommier Y.; Cushman M. (2006). "Synthesis and Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Substituted with Nitrogen Heterocycles". J. Med. Chem. 49 (21): 6283–6289. doi:10.1021/jm060564z. PMC 2526314. PMID 17034134.