GC-Targeted C8-linked pyrrolobenzodiazepine-biaryl conjugates with femtomolar in vitro cytotoxicity and in vivo antitumor activity in mouse models

Journal of Medicinal Chemistry

Volumn 56, Issue 7, 2013, Pages 2911-2935

  Rahman, Khondaker M ^a   Jackson, Paul J M ^a   James, Colin H ^b   Basu, B Piku ^b   Hartley, John A ^c   De La Fuente, Maria ^b   Schatzlein, Andreas ^b   Robson, Mathew ^c   Pedley, R Barbara ^c   Pepper, Chris ^d   Fox, Keith R ^e   Howard, Philip W ^f   Thurston, David E ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY OF LONDON   (United Kingdom)

^c UNIVERSITY COLLEGE LONDON   (United Kingdom)

^d CARDIFF UNIVERSITY   (United Kingdom)

^e UNIVERSITY OF SOUTHAMPTON   (United Kingdom)

^f ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; GWL 78; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; KMR 28 35; KMR 28 39; METHYL 4 [4 (4 ((7 METHOXY 5-OXO 2,3,5,11A TETRAHYDRO 1H PYRROLO[2,1 C][1,4]BENZODIAZEPIN 8 YL)OXY)BUTANAMIDO)PHENYL] 1 METHYL 1H PYRROLE 2 CARBOXYLATE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; BREAST CANCER; CANCER CELL CULTURE; CHRONIC LYMPHATIC LEUKEMIA; DISEASE MODEL; DNA BINDING; DNA SEQUENCE; DRUG CYTOTOXICITY; GC RICH SEQUENCE; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; IN VIVO STUDY; LEUKEMIA CELL; MOUSE; NONHUMAN; TUMOR CELL LINE; TUMOR XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; BENZODIAZEPINES; CELL LINE, TUMOR; DISEASE MODELS, ANIMAL; DRUG SCREENING ASSAYS, ANTITUMOR; FLUORESCENCE RESONANCE ENERGY TRANSFER; GC RICH SEQUENCE; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NF-KAPPA B; SPECTROMETRY, MASS, ELECTROSPRAY IONIZATION;

EID: 84876239511     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301882a     Document Type: Article

References (62)

1. Thurston, D. E. Chemistry and Pharmacology of Anticancer Drugs; CRC Press (Taylor & Francis): Boca Raton, FL, 2006; Vol. 1, pp 283.
2. Dickinson, L. A.; Burnett, R.; Melander, C.; Edelson, B. S.; Arora, P. S.; Dervan, P. B.; Gottesfeld, J. M. Arresting cancer proliferation by small-molecule gene regulation Chem. Biol. 2004, 11, 1583-1594
3. Dervan, P. B. Molecular recognition of DNA by small molecules Bioorg. Med. Chem. 2001, 9, 2215-2235
4. Neidle, S. DNA minor-groove recognition by small molecules Nat. Prod. Rep. 2001, 18, 291-309
5. Smellie, M.; Bose, D. S.; Thompson, A. S.; Jenkins, T. C.; Hartley, J. A.; Thurston, D. E. Sequence-selective recognition of duplex DNA through covalent interstrand cross-linking: kinetic and molecular modeling studies with pyrrolobenzodiazepine dimers Biochemistry 2003, 42, 8232-8239
6. Wells, G.; Martin, C. R. H.; Howard, P. W.; Sands, Z. A.; Laughton, C. A.; Tiberghien, A.; Woo, C. K.; Masterson, L. A.; Stephenson, M. J.; Hartley, J. A.; Jenkins, T. C.; Shnyder, S. D.; Loadman, P. M.; Waring, M. J.; Thurston, D. E. Design, synthesis, and biophysical and biological evaluation of a series of pyrrolobenzodiazepine-poly(N -methylpyrrole) conjugates J. Med. Chem. 2006, 49, 5442-5461
7. Collins, I.; Workman, P. New approaches to molecular cancer therapeutics Nat. Chem. Biol. 2006, 2, 689-700
8. Dervan, P. B.; Burli, R. W. Sequence-specific DNA recognition by polyamides Curr. Opin. Chem. Biol. 1999, 3, 688-693
9. Cipolla, L.; Araujo, A. C.; Airoldi, C.; Bini, D. Pyrrolo[2,1-c][1,4] benzodiazepine as a scaffold for the design and synthesis of anti-tumour drugs Anti-Cancer Agents Med. Chem. 2009, 9, 1-31
10. Thurston, D. E.; Bose, D. S. Synthesis of DNA-interactive pyrrolo[2,1- c ][1,4]benzodiazepines Chem. Rev. 1994, 94, 433-465
11. Antonow, D.; Thurston, D. E. Synthesis of DNA-interactive pyrrolo[2,1- c ][1,4]benzodiazepines (PBDs) Chem. Rev. 2011, 111, 2815-2864
12. Thurston, D. E. Advances in the study of pyrrolo[2,1- c ][1,4]benzodiazepine (PBD) antitumour antibiotics. In Molecular Aspects of Anticancer Drug-DNA Interactions, Neidle, S.; Waring, M. J., Eds.; The Macmillan Press Ltd.: London, 1993; Vol. 1, pp 54-88.
13. Kamal, A.; Rao, M. V.; Laxman, N.; Ramesh, G.; Reddy, G. S. K. Recent developments in the design, synthesis and structure-activity relationship studies of pyrrolo[2,1- c ][1,4]benzodiazepines as DNA-interactive antitumour antibiotics Curr. Med. Chem.: Anti-Cancer Agents 2002, 2, 215-254
14. Rahman, K. M.; Thompson, A. S.; James, C. H.; Narayanaswamy, M.; Thurston, D. E. The pyrrolobenzodiazepine dimer SJG-136 forms sequence-dependent intrastrand DNA cross-links and monoalkylated adducts in addition to interstrand cross-links J. Am. Chem. Soc. 2009, 131, 13756-13766
15. Gregson, S. J.; Howard, P. W.; Hartley, J. A.; Brooks, N. A.; Adams, L. J.; Jenkins, T. C.; Kelland, L. R.; Thurston, D. E. Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity J. Med. Chem. 2001, 44, 737-748
16. Rahman, K. M.; James, C. H.; Bui, T. T. T.; Drake, A. F.; Thurston, D. E. Observation of a single-stranded DNA/pyrrolobenzodiazepine adduct J. Am. Chem. Soc. 2011, 133, 19376-19385
17. Rahman, K. M.; James, C. H.; Thurston, D. E. Effect of base sequence on the DNA cross-linking properties of pyrrolobenzodiazepine (PBD) dimers Nucleic Acids Res. 2011, 39, 5800-5812
18. Janjigian, Y. Y.; Lee, W.; Kris, M. G.; Miller, V. A.; Krug, L. M.; Azzoli, C. G.; Senturk, E.; Calcutt, M. W.; Rizvi, N. A. A phase I trial of SJG-136 (NSC#694501) in advanced solid tumors Cancer Chemother. Pharmacol. 2010, 65, 833-838
19. Narendran, A.; Jayanthan, A.; Singh, A.; Incoronato, A.; Desai, S.; Whitlock, J. SJG-136 (NSC 694501), a unique DNA minor groove interstrand cross-linking agent shows significant activity and drug combinability against aggressive type of pediatric leukemia Pediatr. Blood Cancer 2010, 54, 814-814
20. Hochhauser, D.; Meyer, T.; Spanswick, V. J.; Wu, J.; Clingen, P. H.; Loadman, P. M.; Cobb, M.; Gumbrell, L.; Begent, R. H. J.; Hartley, J. A.; Jodrell, D. I. Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors Clin. Cancer Res. 2009, 15, 2140-2147
21. Rahman, K. M.; James, C. H.; Thurston, D. E. Observation of the reversibility of a covalent pyrrolobenzodiazepine (PBD) DNA adduct by HPLC/MS and CD spectroscopy Org. Biomol. Chem. 2011, 9, 1632-1641
22. Rahman, K. M.; Vassoler, H.; James, C. H.; Thurston, D. E. DNA sequence preference and adduct orientation of pyrrolo[2,1- c ][1,4]benzodiazepine antitumor agents ACS Med. Chem. Lett. 2010, 1, 427-432
23. Kamal, A.; Rajender; Reddy, D. R.; Reddy, M. K.; Balakishan, G.; Shaik, T. B.; Chourasia, M.; Sastry, G. N. Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2,1- c ][1,4]benzodiazepines and their anticancer potential Bioorg. Med. Chem. 2009, 17, 1557-1572
24. Puvvada, M. S.; Hartley, J. A.; Jenkins, T. C.; Thurston, D. E. A quantitative assay to measure the relative DNA-binding affinity of pyrrolo[2,1-c][1,4]benzodizepine (PBD) antitumour antibiotics based on the inhibition of restriction endonuclease BamHI Nucleic Acids Res. 1993, 21, 3671-3675
25. Puvvada, M. S.; Forrow, S. A.; Hartley, J. A.; Stephenson, P.; Gibson, I.; Jenkins, T. C.; Thurston, D. E. Inhibition of bacteriophage T7 RNA polymerase in vitro transcription by DNA-binding pyrrolo[2,1- c ][1,4]benzodiazepines Biochemistry 1997, 36, 2478-2484
26. Kotecha, M.; Kluza, J.; Wells, G.; O'Hare, C. C.; Forni, C.; Mantovani, R.; Howard, P. W.; Morris, P.; Thurston, D. E.; Hartley, J. A.; Hochhauser, D. Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78 Mol. Cancer Ther. 2008, 7, 1319-1328
27. Hsieh, M.-C.; Hu, W.-P.; Yu, H.-S.; Wu, W.-C.; Chang, L.-S.; Kao, Y.-H.; Wang, J.-J. A DC-81-indole conjugate agent suppresses melanoma A375 cell migration partially via interrupting VEGF production and stromal cell-derived factor-1α-mediated signaling Toxicol. Appl. Pharmacol. 2011, 255, 150-159
28. Andreassen, P. R.; Ren, K. Q. Fanconi anemia proteins, DNA interstrand crosslink repair pathways, and cancer therapy Curr. Cancer Drug Targets 2009, 9, 101-117
29. Hartley, J.; Hamaguchi, A.; Suggitt, M.; Gregson, S.; Thurston, D.; Howard, P. DNA interstrand cross-linking and in vivo antitumor activity of the extended pyrrolo[2,1- c ][1,4]benzodiazepine dimer SG2057 Invest. New Drugs 2012, 30, 950-958
30. Osada, H.; Uramoto, M.; Uzawa, J.; Kajikawa, K.; Isono, K. New pyrrolobenzodiazepine antibiotics, RK-1441 A and B. II. Isolation and structure Agric. Biol. Chem. 1990, 54, 2883-2887
31. Hadjivassileva, T.; Thurston, D. E.; Taylor, P. W. Pyrrolobenzodiazepine dimers: novel sequence-selective, DNA-interactive, cross-linking agents with activity against Gram-positive bacteria J. Antimicrob. Chemother. 2005, 56, 513-518
32. Fotso, S. Naturally occuring pyrrolo[1,4]benzodiazepines in bacteria Mini-Rev. Org. Chem. 2010, 7, 68-74
33. Fotso, S.; Zabriskie, T. M.; Proteau, P. J.; Flatt, P. M.; Santosa, D. A.; Sulastri; Mahmud, T. Limazepines A-F, pyrrolo[1,4]benzodiazepine antibiotics from an Indonesian Micrococcus sp J. Nat. Prod. 2009, 72, 690-695
34. Rahman, K. M.; Rosado, H.; Moreira, J. B.; Feuerbaum, E.-A.; Fox, K. R.; Stecher, E.; Howard, P. W.; Gregson, S. J.; James, C. H.; de la Fuente, M.; Waldron, D. E.; Thurston, D. E.; Taylor, P. W. Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates J. Antimicrob. Chemother. 2012, 67, 1683-1696
35. Rosado, H.; Rahman, K. M.; Feuerbaum, E.-A.; Hinds, J.; Thurston, D. E.; Taylor, P. W. The minor groove-binding agent ELB-21 forms multiple interstrand and intrastrand covalent cross-links with duplex DNA and displays potent bactericidal activity against methicillin-resistant Staphylococcus aureus J. Antimicrob. Chemother. 2011, 66, 985-996
36. Boger, D. L.; Fink, B. E.; Brunette, S. R.; Tse, W. C.; Hedrick, M. P. A simple, high-resolution method for establishing DNA binding affinity and sequence selectivity J. Am. Chem. Soc. 2001, 123, 5878-5891
37. Narayanaswamy, M.; Griffiths, W. J.; Howard, P. W.; Thurston, D. E. An assay combining high-performance liquid chromatography and mass spectrometry to measure DNA interstrand cross-linking efficiency in oligonucleotides of varying sequences Anal. Biochem. 2008, 374, 173-181
38. Organ MG, D. C.; Mayhew, D.; Parks, D. J.; Arvanitis, E. A. The use of a supported base and strong cation exchange (SCX) chromatography to prepare a variety of structurally-diverse molecular libraries prepared by solution-phase methods Comb. Chem. High Throughput Screening 2002, 5, 211-218
39. Tse, W. C.; Boger, D. L. A fluorescent intercalator displacement assay for establishing DNA binding selectivity and affinity Acc. Chem. Res. 2004, 37, 61-69
40. Jenkins, T. C.; Hurley, L. H.; Neidle, S.; Thurston, D. E. Structure of a covalent DNA minor-groove adduct with a pyrrolobenzodiazepine dimer: evidence for sequence-specific interstrand cross-linking J. Med. Chem. 1994, 37, 4529-4537
41. Hampshire, A. J.; Fox, K. R. Preferred binding sites for the bifunctional intercalator TANDEM determined using DNA fragments that contain every symmetrical hexanucleotide sequence Anal. Biochem. 2008, 374, 298-303
42. Thurston, D. E.; Murty, V. S.; Langley, D. R.; Jones, G. B. O -Debenzylation of a pyrrolo[2,1- c ][1,4]benzodiazepine in the presence of a carbinolamine functionality: synthesis of DC-81 Synthesis 1990, 81-84
43. Skehan P, S. R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. New colorimetric cytotoxicity assay for anticancer-drug screening J. Natl. Cancer Inst. 1990, 82, 1107-1112
44. van Engeland, M.; Nieland, L. J. W.; Ramaekers, F. C. S.; Schutte, B.; Reutelingsperger, C. P. M. Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure Cytometry 1998, 31, 1-9
45. Hartley, J. A.; Spanswick, V. J.; Brooks, N.; Clingen, P. H.; McHugh, P. J.; Hochhauser, D.; Pedley, R. B.; Kelland, L. R.; Alley, M. C.; Schultz, R.; Hollingshead, M. G.; Schweikart, K. M.; Tomaszewski, J. E.; Sausville, E. A.; Gregson, S. J.; Howard, P. W.; Thurston, D. E. SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity Cancer Res. 2004, 64, 6693-6699
46. Pepper, C. J.; Hambly, R. M.; Fegan, C. D.; Delavault, P.; Thurston, D. E. The novel sequence-specific DNA cross-linking agent SJG-136 (NSC 694501) has potent and selective in vitro cytotoxicity in human B-cell chronic lymphocytic leukemia cells with evidence of a p53-independent mechanism of cell kill Cancer Res. 2004, 64, 6750-6755
47. Pepper, C.; Lowe, H.; Fegan, C.; Thurieau, C.; Thurston, D. E.; Hartley, J. A.; Delavault, P. Fludarabine-mediated suppression of the excision repair enzyme ERCC1 contributes to the cytotoxic synergy with the DNA minor groove crosslinking agent SJG-136 (NSC 694501) in chronic lymphocytic leukaemia cells Br. J. Cancer 2007, 97, 253-259
48. Hu, W.-P.; Tsai, F.-Y.; Yu, H.-S.; Sung, P.-J.; Chang, L.-S.; Wang, J.-J. Induction of apoptosis by DC-81-indole conjugate agent through NF-κB and JNK/AP-1 pathway Chem. Res. Toxicol. 2008, 21, 1330-1336
49. Brucoli, F.; Hawkins, R. M.; James, C. H.; Wells, G.; Jenkins, T. C.; Ellis, T.; Hartley, J. A.; Howard, P. W.; Thurston, D. E. Novel C8-linked pyrrolobenzodiazepine (PBD)-heterocycle conjugates that recognize DNA sequences containing an inverted CCAAT box Bioorg. Med. Chem. Lett. 2011, 21, 3780-3783
50. Borgatti, M.; Rutigliano, C.; Bianchi, N.; Mischiati, C.; Baraldi, P. G.; Romagnoli, R.; Gambari, R. Inhibition of NF-kB/DNA interactions and HIV-1 LTR directed transcription by hybrid molecules containing pyrrolo [2,1- c ] [1,4] benzodiazepine (PRD) and oligopyrrole carriers Drug Dev. Res. 2003, 60, 173-185
51. Baraldi, P. G.; Cacciari, B.; Guiotto, A.; Romagnoli, R.; Spalluto, G.; Leoni, A.; Bianchi, N.; Feriotto, G.; Rutigliano, C.; Mischiati, C.; Gambari, R. [2,1-c][1,4]Benzodiazepine (PBD)-distamycin hybrid inhibits DNA binding to transcription factor Sp1 Nucleosides, Nucleotides Nucleic Acids 2000, 19, 1219-1229
52. Harhaj, E. W.; Sun, S. C. IKKγ serves as a docking subunit of the IκB kinase (IKK) and mediates interaction of IKK with the human T-cell leukemia virus Tax protein J. Biol. Chem. 1999, 274, 22911-22914
53. Mori, N.; Fujii, M.; Ikeda, S.; Yamada, Y.; Tomonaga, M.; Ballard, D. W.; Yamamoto, N. Constitutive activation of NF-κB in primary adult T-cell leukemia cells Blood 1999, 93, 2360-2368
54. Pepper, C.; Hewamana, S.; Brennan, P.; Fegan, C. NF-κB as a prognostic marker and therapeutic target in chronic lymphocytic leukemia Future Oncol. 2009, 5, 1027-1037
55. Karin, M.; Lin, A. NF-κB at the crossroads of life and death Nat. Immunol. 2002, 3, 221-227
56. Wang, C.-Y.; Cusack, J. C.; Liu, R.; Baldwin, A. S. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-κB Nat. Med. 1999, 5, 412-417
57. Baird, E. E.; Dervan, P. B. Solid phase synthesis of polyamides containing imidazole and pyrrole amino acids J. Am. Chem. Soc. 1996, 118, 6141-6146
58. Case, D. A.; Darden, T. A.; Cheatham, T. E., III; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Walker, R. C.; Zhang, W.; Merz, K. M.; Roberts, B.; Wang, B.; Hayik, S.; Roitberg, A.; Seabra, G.; Kolossváry, I.; Wong, K. F.; Paesani, F.; Vanicek, J.; Liu, J.; Wu, X.; Brozell, S. R.; Steinbrecher, T.; Gohlke, H.; Cai, Q.; Ye, X.; Wang, J.; Hsieh, M.-J.; Cui, G.; Roe, D. R.; Mathews, D. H.; Seetin, M. G.; Sagui, C.; Babin, V.; Luchko, T.; Gusarov, S.; Kovalenko, A.; Kollman, P. A. AMBER 11; University of California: San Francisco, 2010.
59. Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF chimera-a visualization system for exploratory research and analysis J. Comput. Chem. 2004, 25, 1605-1612
60. Hampshire, A. J.; Rusling, D. A.; Broughton-Head, V. J.; Fox, K. R. Footprinting: a method for determining the sequence selectivity, affinity and kinetics of DNA-binding ligands Methods 2007, 42, 128-140
61. Workman, P.; Aboagye, E. O.; Balkwill, F.; Balmain, A.; Bruder, G.; Chaplin, D. J.; Double, J. A.; Everitt, J.; Farningham, D. A. H.; Glennie, M. J.; Kelland, L. R.; Robinson, V.; Stratford, I. J.; Tozer, G. M.; Watson, S.; Wedge, S. R.; Eccles, S. A. Guidelines for the welfare and use of animals in cancer research Br. J. Cancer 2010, 102, 1555-1577
62. Tomayko, M. M.; Reynolds, C. P. Determination of subcutaneous tumor size in athymic (nude) mice Cancer Chemother. Pharmacol. 1989, 24, 148-154