Development of Small Molecules that Specifically Inhibit the D-loop Activity of RAD51

Journal of Medicinal Chemistry

Volumn 59, Issue 10, 2016, Pages 4511-4525

  Lv, Wei ^a   Budke, Brian ^b   Pawlowski, Michal ^a   Connell, Philip P ^b   Kozikowski, Alan P ^a  

^a UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

^b UNIVERSITY OF CHICAGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 (PYRROLO[1,2 A]QUINOXALIN 4 YL)ANILINE; 4 (3 NITROPHENYL)PYRROLO[1,2 A]QUINOXALINE; 4 (4 HYDROXYPHENYL)PYRROLO[1,2 A]QUINOXALIN 7 OL; 4 (4 NITROPHENYL)PYRROLO[1,2 A]QUINOXALIN 7 OL; 4 (4 NITROPHENYL)PYRROLO[1,2 A]QUINOXALINE; 4 (7 FLUOROPYRROLO[1,2 A]QUINOXALIN 4 YL) N,N DIMETHYLANILINE; 4 (7 METHOXY 4,5 DIHYDROPYRROLO[1,2 ALPHA]QUINOXALIN 4 YL) N,N DIMETHYLANILINE; 4 (7 METHOXYPYRROLO[1,2 A]QUINOXALIN 4 YL)PHENOL; 4 (7,8 DIFLUOROPYRROLO[1,2 A]QUINOXALIN 4 YL) N,N DIMETHYLANILINE; 4 (CYCLOHEX 1 EN 1 YL)PYRROLO[1,2 A]QUINOXALINE; 4 (NAPHTHALEN 1 YL)PYRROLO[1,2 A]QUINOXALINE; 4 (PYRIDIN 3 YL)PYRROLO[1,2 A]QUINOXALIN 7 OL; 4 (PYRIDIN 3 YL)PYRROLO[1,2 A]QUINOXALINE; 4 (PYRIDIN 4 YL)PYRROLO[1,2 A]QUINOXALINE; 4 (PYRROLO[1,2 A]QUINOXALIN 4 YL)ANILINE; 4 (PYRROLO[1,2 A]QUINOXALIN 4 YL)PHENOL; 4 [4 (DIMETHYLAMINO)PHENYL]PYRROLO[1,2 A]QUINOXALIN 7 OL; 4 [4 (PYRROLIDIN 1 YL)PHENYL]PYRROLO[1,2 A]QUINOXALINE; 4 [4 (PYRROLO[1,2 A]QUINOXALIN 4 YL)PHENYL]MORPHOLINE; 4 [4 (TRIFLUOROMETHOXY)PHENYL]PYRROLO[1,2 A]QUINOXALINE; 7 FLUORO 4 (4 NITROPHENYL)PYRROLO[1,2 A]QUINOXALINE; 7 METHOXY 4 (4 NITROPHENYL)PYRROLO[1,2 A]QUINOXALINE; 7 METHOXY 4 (PYRIDIN 3 YL)PYRROLO[1,2 A]QUINOXALINE; 7,8 DIFLUORO 4 (4 NITROPHENYL)PYRROLO[1,2 A]QUINOXALINE; N ETHYL 4 (PYRROLO[1,2 A]QUINOXALIN 4 YL)ANILINE; N,N DIMETHYL 4 (PYRROLO[1,2 A]QUINOXALIN 4 YL)ANILINE; N,N DIMETHYLANILINE; RAD51 PROTEIN; SINGLE STRANDED DNA; UNCLASSIFIED DRUG; UNINDEXED DRUG; MOLECULAR LIBRARY; RAD51 PROTEIN, HUMAN;

ARTICLE; DNA DAMAGE; HIGH THROUGHPUT SCREENING; HOMOLOGOUS RECOMBINATION; HUMAN; HUMAN CELL; HYDROGENATION; IC50; OXIDATION; PROTEIN DNA BINDING; RECOMBINATION REPAIR; STRUCTURE ACTIVITY RELATION; ANTAGONISTS AND INHIBITORS; CELL LINE; CELL SURVIVAL; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG EFFECTS; METABOLISM; MOLECULAR LIBRARY; PHARMACOLOGY; SYNTHESIS;

CELL LINE; CELL SURVIVAL; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; MOLECULAR STRUCTURE; RAD51 RECOMBINASE; SMALL MOLECULE LIBRARIES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84971623143     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01762     Document Type: Article

References (38)

1. Thompson, L. H.; Schild, D. Homologous Recombinational Repair of DNA Ensures Mammalian Chromosome Stability Mutat. Res., Fundam. Mol. Mech. Mutagen. 2001, 477, 131-153 10.1016/S0027-5107(01)00115-4
2. Tebbs, R. S.; Zhao, Y.; Tucker, J. D.; Scheerer, J. B.; Siciliano, M. J.; Hwang, M.; Liu, N.; Legerski, R. J.; Thompson, L. H. Correction of Chromosomal Instability and Sensitivity to Diverse Mutagens by a Cloned Cdna of the Xrcc3 DNA Repair Gene Proc. Natl. Acad. Sci. U. S. A. 1995, 92, 6354-6358 10.1073/pnas.92.14.6354
3. Liu, N.; Lamerdin, J. E.; Tebbs, R. S.; Schild, D.; Tucker, J. D.; Shen, M. R.; Brookman, K. W.; Siciliano, M. J.; Walter, C. A.; Fan, W.; Narayana, L. S.; Zhou, Z. Q.; Adamson, A. W.; Sorensen, K. J.; Chen, D. J.; Jones, N. J.; Thompson, L. H. Xrcc2 and Xrcc3, New Human Rad51-Family Members, Promote Chromosome Stability and Protect against DNA Cross-Links and Other Damages Mol. Cell 1998, 1, 783-793 10.1016/S1097-2765(00)80078-7
4. Takata, M.; Sasaki, M. S.; Tachiiri, S.; Fukushima, T.; Sonoda, E.; Schild, D.; Thompson, L. H.; Takeda, S. Chromosome Instability and Defective Recombinational Repair in Knockout Mutants of the Five Rad51 Paralogs Mol. Cell. Biol. 2001, 21, 2858-2866 10.1128/MCB.21.8.2858-2866.2001
5. Klein, H. L. The Consequences of Rad51 Overexpression for Normal and Tumor Cells DNA Repair 2008, 7, 686-693 10.1016/j.dnarep.2007.12.008
6. Hine, C. M.; Seluanov, A.; Gorbunova, V. Use of the Rad51 Promoter for Targeted Anti-Cancer Therapy Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 20810-20815 10.1073/pnas.0807990106
7. Vispe, S.; Cazaux, C.; Lesca, C.; Defais, M. Overexpression of Rad51 Protein Stimulates Homologous Recombination and Increases Resistance of Mammalian Cells to Ionizing Radiation Nucleic Acids Res. 1998, 26, 2859-2864 10.1093/nar/26.12.2859
8. Slupianek, A.; Schmutte, C.; Tombline, G.; Nieborowska-Skorska, M.; Hoser, G.; Nowicki, M. O.; Pierce, A. J.; Fishel, R.; Skorski, T. Bcr/Abl Regulates Mammalian Reca Homologs, Resulting in Drug Resistance Mol. Cell 2001, 8, 795-806 10.1016/S1097-2765(01)00357-4
9. Bello, V. E.; Aloyz, R. S.; Christodoulopoulos, G.; Panasci, L. C. Homologous Recombinational Repair Vis-a-Vis Chlorambucil Resistance in Chronic Lymphocytic Leukemia Biochem. Pharmacol. 2002, 63, 1585-1588 10.1016/S0006-2952(02)00954-1
10. Hansen, L. T.; Lundin, C.; Spang-Thomsen, M.; Petersen, L. N.; Helleday, T. The Role of Rad51 in Etoposide (Vp16) Resistance in Small Cell Lung Cancer Int. J. Cancer 2003, 105, 472-479 10.1002/ijc.11106
11. Russell, J. S.; Brady, K.; Burgan, W. E.; Cerra, M. A.; Oswald, K. A.; Camphausen, K.; Tofilon, P. J. Gleevec-Mediated Inhibition of Rad51 Expression and Enhancement of Tumor Cell Radiosensitivity Cancer Res. 2003, 63, 7377-7383
12. Ito, M.; Yamamoto, S.; Nimura, K.; Hiraoka, K.; Tamai, K.; Kaneda, Y. Rad51 Sirna Delivered by Hvj Envelope Vector Enhances the Anti-Cancer Effect of Cisplatin J. Gene Med. 2005, 7, 1044-1052 10.1002/jgm.753
13. Budke, B.; Logan, H. L.; Kalin, J. H.; Zelivianskaia, A. S.; Cameron McGuire, W.; Miller, L. L.; Stark, J. M.; Kozikowski, A. P.; Bishop, D. K.; Connell, P. P. Ri-1: A Chemical Inhibitor of Rad51 That Disrupts Homologous Recombination in Human Cells Nucleic Acids Res. 2012, 40, 7347-7357 10.1093/nar/gks353
14. Renodon-Cornière, A.; Weigel, P.; Le Breton, M.; Fleury, F. New Potential Therapeutic Approaches by Targeting Rad51-Dependent Homologous Recombination. In New Research Directions in DNA Repair; Chen, C., Ed.; InTech: Rijeka, Croatia, 2013.
15. Carvalho, J. F.; Kanaar, R. Targeting Homologous Recombination-Mediated DNA Repair in Cancer Expert Opin. Ther. Targets 2014, 18, 427-458 10.1517/14728222.2014.882900
16. Huang, F.; Mazin, A. V. Targeting the Homologous Recombination Pathway by Small Molecule Modulators Bioorg. Med. Chem. Lett. 2014, 24, 3006-3013 10.1016/j.bmcl.2014.04.088
17. Huang, F.; Mazina, O. M.; Zentner, I. J.; Cocklin, S.; Mazin, A. V. Inhibition of Homologous Recombination in Human Cells by Targeting Rad51 Recombinase J. Med. Chem. 2012, 55, 3011-3020 10.1021/jm201173g
18. Ishida, T.; Takizawa, Y.; Kainuma, T.; Inoue, J.; Mikawa, T.; Shibata, T.; Suzuki, H.; Tashiro, S.; Kurumizaka, H. Dids, a Chemical Compound That Inhibits Rad51-Mediated Homologous Pairing and Strand Exchange Nucleic Acids Res. 2009, 37, 3367-3376 10.1093/nar/gkp200
19. Budke, B.; Kalin, J. H.; Pawlowski, M.; Zelivianskaia, A. S.; Wu, M.; Kozikowski, A. P.; Connell, P. P. An Optimized Rad51 Inhibitor That Disrupts Homologous Recombination without Requiring Michael Acceptor Reactivity J. Med. Chem. 2013, 56, 254-263 10.1021/jm301565b
20. Takaku, M.; Kainuma, T.; Ishida-Takaku, T.; Ishigami, S.; Suzuki, H.; Tashiro, S.; van Soest, R. W.; Nakao, Y.; Kurumizaka, H. Halenaquinone, a Chemical Compound That Specifically Inhibits the Secondary DNA Binding of Rad51 Genes Cells 2011, 16, 427-436 10.1111/j.1365-2443.2011.01494.x
21. Schlacher, K.; Christ, N.; Siaud, N.; Egashira, A.; Wu, H.; Jasin, M. Double-Strand Break Repair-Independent Role for Brca2 in Blocking Stalled Replication Fork Degradation by Mre11 Cell 2011, 145, 529-542 10.1016/j.cell.2011.03.041
22. Ying, S.; Hamdy, F. C.; Helleday, T. Mre11-Dependent Degradation of Stalled DNA Replication Forks Is Prevented by Brca2 and Parp1 Cancer Res. 2012, 72, 2814-2821 10.1158/0008-5472.CAN-11-3417
23. Jayathilaka, K.; Sheridan, S. D.; Bold, T. D.; Bochenska, K.; Logan, H. L.; Weichselbaum, R. R.; Bishop, D. K.; Connell, P. P. A Chemical Compound That Stimulates the Human Homologous Recombination Protein Rad51 Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 15848-15853 10.1073/pnas.0808046105
24. Budke, B.; Chan, Y. L.; Bishop, D. K.; Connell, P. P. Real-Time Solution Measurement of Rad51- and Reca-Mediated Strand Assimilation without Background Annealing Nucleic Acids Res. 2013, 41, e130 10.1093/nar/gkt362
25. Cheng, J.; Giguere, P. M.; Onajole, O. K.; Lv, W.; Gaisin, A.; Gunosewoyo, H.; Schmerberg, C. M.; Pogorelov, V. M.; Rodriguiz, R. M.; Vistoli, G.; Wetsel, W. C.; Roth, B. L.; Kozikowski, A. P. Optimization of 2-Phenylcyclopropylmethylamines as Selective Serotonin 2c Receptor Agonists and Their Evaluation as Potential Antipsychotic Agents J. Med. Chem. 2015, 58, 1992-2002 10.1021/jm5019274
26. Cheng, J.; Giguere, P. M.; Lv, W.; Roth, B. L.; Kozikowski, A. P. Design and Synthesis of (2-(5-Chloro-2,2-Dimethyl-2,3-Dihydrobenzofuran-7-Yl)Cyclopropyl)Methanamine as a Selective Serotonin 2c Agonist Tetrahedron Lett. 2015, 56, 3420-3422 10.1016/j.tetlet.2015.01.060
27. Bennardo, N.; Cheng, A.; Huang, N.; Stark, J. M. Alternative-Nhej Is a Mechanistically Distinct Pathway of Mammalian Chromosome Break Repair PLoS Genet. 2008, 4, e1000110 10.1371/journal.pgen.1000110
28. Stark, J. M.; Pierce, A. J.; Oh, J.; Pastink, A.; Jasin, M. Genetic Steps of Mammalian Homologous Repair with Distinct Mutagenic Consequences Mol. Cell. Biol. 2004, 24, 9305-9316 10.1128/MCB.24.21.9305-9316.2004
29. Raderschall, E.; Stout, K.; Freier, S.; Suckow, V.; Schweiger, S.; Haaf, T. Elevated Levels of Rad51 Recombination Protein in Tumor Cells Cancer Res. 2002, 62, 219-225
30. Guillon, J.; Grellier, P.; Labaied, M.; Sonnet, P.; Leger, J. M.; Deprez-Poulain, R.; Forfar-Bares, I.; Dallemagne, P.; Lemaitre, N.; Pehourcq, F.; Rochette, J.; Sergheraert, C.; Jarry, C. Synthesis, Antimalarial Activity, and Molecular Modeling of New Pyrrolo[1,2-a]Quinoxalines, Bispyrrolo[1,2-a]Quinoxalines, Bispyrido[3,2-E]Pyrrolo[1,2-a]Pyrazines, and Bispyrrolo[1,2-a]Thieno[3,2-E]Pyrazines J. Med. Chem. 2004, 47, 1997-2009 10.1021/jm0310840
31. Campiani, G.; Morelli, E.; Gemma, S.; Nacci, V.; Butini, S.; Hamon, M.; Novellino, E.; Greco, G.; Cagnotto, A.; Goegan, M.; Cervo, L.; Dalla Valle, F.; Fracasso, C.; Caccia, S.; Mennini, T. Pyrroloquinoxaline Derivatives as High-Affinity and Selective 5-Ht(3) Receptor Agonists: Synthesis, Further Structure-Activity Relationships, and Biological Studies J. Med. Chem. 1999, 42, 4362-4379 10.1021/jm990151g
32. Preetam, A.; Nath, M. An Eco-Friendly Pictet-Spengler Approach to Pyrrolo- and Indolo[1,2-a]Quinoxalines Using P-Dodecylbenzenesulfonic Acid as an Efficient Bronsted Acid Catalyst RSC Adv. 2015, 5, 21843-21853 10.1039/C4RA16651E
33. Guillon, J.; Forfar, I.; Mamani-Matsuda, M.; Desplat, V.; Saliege, M.; Thiolat, D.; Massip, S.; Tabourier, A.; Leger, J. M.; Dufaure, B.; Haumont, G.; Jarry, C.; Mossalayi, D. Synthesis, Analytical Behaviour and Biological Evaluation of New 4-Substituted Pyrrolo[1,2-a]Quinoxalines as Antileishmanial Agents Bioorg. Med. Chem. 2007, 15, 194-210 10.1016/j.bmc.2006.09.068
34. Wang, C.; Li, Y.; Guo, R.; Tian, J.; Tao, C.; Cheng, B.; Wang, H.; Zhang, J.; Zhai, H. Iodine-Catalyzed Facile Synthesis of Pyrrolo- and Indolo[1,2-a]Quinoxalines Asian J. Org. Chem. 2015, 4, 866-869 10.1002/ajoc.201500174
35. Cloud, V.; Chan, Y. L.; Grubb, J.; Budke, B.; Bishop, D. K. Rad51 Is an Accessory Factor for Dmc1-Mediated Joint Molecule Formation During Meiosis Science 2012, 337, 1222-1225 10.1126/science.1219379
36. Sikorski, R. S.; Hieter, P. A System of Shuttle Vectors and Yeast Host Strains Designed for Efficient Manipulation of DNA in Saccharomyces Cerevisiae Genetics 1989, 122, 19-27
37. R Core Team. R: A Language and Environment for Statistical Computing; R Foundation for Statistical Computing, 2015.
38. Eklund, A. The Bee Swarm Plot, an Alternative to Stripchart; 2015.