Polyamine transport inhibitors: Design, synthesis, and combination therapies with difluoromethylornithine

Journal of Medicinal Chemistry

Volumn 57, Issue 2, 2014, Pages 348-363

  Muth, Aaron ^a   Madan, Meenu ^a   Archer, Jennifer Julian ^a   Ocampo, Nicolette ^a   Rodriguez, Luis ^a   Phanstiel, Otto ^a  

^a UNIVERSITY OF CENTRAL FLORIDA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,6 DIAMINO N [3 [[4 [(3 AMINOPROPYL)AMINO]BUTYL]AMINO]PROPYL]HEXANAMIDE; AMINE OXIDASE (FLAVIN CONTAINING); ANTINEOPLASTIC ALKALOID; BENZENE DERIVATIVE; EFLORNITHINE; N 1, N 1 ' [1,3 PHENYLENEBIS(METHYLENE)]BIS[N 4 [4 [(4 AMINOBUTYL)AMINO]BUTYL]BUTANE 1,4 DIAMINE]; N 1, N 1 ', N 1 '' [BENZENE 1,3,5 TRIYLTRIS(METHYLENE)]TRIS[N 4 (4 AMINOBUTYL)BUTANE 1,4 DIAMINE]; N 1, N 1' [1,3 PHENYLENEBIS(METHYLENE)]BIS[N 4 (4 AMINOBUTYL)BUTANE 1,4 DIAMINE]; N 1, N 3, N 5 TRIS[3 [[4 [(3 AMINOPROPYL)AMINO]BUTYL]AMINO]PROPYL]BENZENE 1,3,5 TRICARBOXAMIDE NONHYDROCHLORIDE; N 1, N 3, N 5 TRIS[4 [(4 AMINOBUTYL)AMINO]BUTYL]BENZENE 1,3,5 TRICARBOXAMIDE; N 1, N 3, N 5 TRIS[4 [[4 [(4 AMINOBUTYL)AMINO]BUTYL]AMINO]BUTYL]BENZENE 1,3,5 TRICARBOXAMIDE NONAHYDROCHLORIDE; N 1,N 1 ',N 1 '' [BENZENE 1,3,5 TRIYLTRIS(METHYLENE)]TRIS[N 4 [4 (METHYLAMINO)BUTYL]BUTANE 1,4 DIAMINE]; POLYAMINE DERIVATIVE; SPERMIDINE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; CANCER CELL CULTURE; CANCER COMBINATION CHEMOTHERAPY; CELL DEATH; CONTROLLED STUDY; DRUG CYTOTOXICITY; DRUG DESIGN; DRUG POTENCY; DRUG SYNTHESIS; FEMALE; HUMAN; HUMAN TISSUE; NONHUMAN; PANCREAS CANCER;

ANIMALS; ANTINEOPLASTIC AGENTS; BENZENE DERIVATIVES; BIOLOGICAL TRANSPORT; CELL LINE, TUMOR; CHO CELLS; CRICETINAE; CRICETULUS; DRUG DESIGN; DRUG SCREENING ASSAYS, ANTITUMOR; DRUG SYNERGISM; EFLORNITHINE; HUMANS; OXIDOREDUCTASES ACTING ON CH-NH GROUP DONORS; PANCREATIC NEOPLASMS; POLYAMINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84893079505     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401174a     Document Type: Article

References (67)

1. Cullis, P. M.; Green, R. E.; Merson-Davies, L.; Travis, N. Probing the mechanism of transport and compartmentalization of polyamines in mammalian cells Chem. Biol. 1999, 6, 717-729 (Pubitemid 29485534)
2. Seiler, N.; Delcros, J.-G.; Moulinoux, J. P. Polyamine transport in mammalian cells. An update Int. J. Biochem. 1996, 28, 843-861 (Pubitemid 26284212)
3. Seiler, N.; Dezeure, F. Polyamine transport in mammalian cells Int. J. Biochem. 1990, 22, 211-218 (Pubitemid 20199939)
4. Casero, R. A.; Marton, L. J. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases Nat. Rev. Drug Discovery 2007, 6, 373-390 (Pubitemid 46705201)
5. Coffino, P. Regulation of cellular polyamines by antizyme Nat. Rev. Mol. Cell Biol. 2001, 2 (3) 188-194 (Pubitemid 33675743)
6. Phanstiel, O.; Price, H. L.; Wang, L.; Juusola, J.; Kline, M.; Shah, S. M. The effect of polyamine homologation on the transport and cytotoxicity properties of polyamine-(DNA intercalator) conjugates J. Org. Chem. 2000, 65, 5590-5599
7. Wang, L.; Price, H. L.; Juusola, J.; Kline, M.; Phanstiel, O., IV. Influence of polyamine architecture on the transport and topoisomerase II inhibitory properties of polyamine DNA-intercalator conjugates J. Med. Chem. 2001, 44, 3682-3691 (Pubitemid 33026676)
8. Wang, C.; Delcros, J.-G.; Biggerstaff, J.; Phanstiel, O. Synthesis and biological evaluation of N 1-(anthracen-9-ylmethyl)triamines as molecular recognition elements for the polyamine transporter J. Med. Chem. 2003, 46, 2663-2671 (Pubitemid 36702535)
9. Wang, C.; Delcros, J.-G.; Biggerstaff, J.; Phanstiel, O. Molecular requirements for targeting the polyamine transport system: Synthesis and biological evaluation of polyamine anthracene conjugates J. Med. Chem. 2003, 46, 2672-2682 (Pubitemid 36702536)
10. Wang, C.; Delcros, J.-G.; Cannon, L.; Konate, F.; Carias, H.; Biggerstaff, J.; Gardner, R. A.; Phanstiel, O. Defining the molecular requirements for the selective delivery of polyamine conjugates into cells containing active polyamine transporters J. Med. Chem. 2003, 46, 5129-5138 (Pubitemid 37414183)
11. Kaur, N.; Delcros, J.-G.; Martin, B.; Phanstiel, O. Synthesis and biological evaluation of dihydromotuporamine derivatives in cells containing active polyamine transporters J. Med. Chem. 2005, 48, 3832-3839 (Pubitemid 40776858)
12. Gardner, R. A.; Delcros, J.-G.; Konate, F.; Breitbeil, F.; Martin, B.; Sigman, M.; Phanstiel, O. N 1-Substituent effects in the selective delivery of polyamine-conjugates into cells containing active polyamine transporters J. Med. Chem. 2004, 47, 6055-6069 (Pubitemid 39507347)
13. Barret, J. M.; Kruczynski, A.; Vispe, S.; Annereau, J. P.; Brel, V.; Guminski, Y.; Delcros, J. G.; Lansiaux, A.; Guilbaud, N.; Imbert, T.; Bailly, C. F14512, a potent antitumor agent targeting topoisomerase II vectored into cancer cells via the polyamine transport system Cancer Res. 2008, 68 (23) 9845-9853
14. Kruczynski, A.; Pillon, A.; Creancier, L.; Vandenberghe, I.; Gomes, B.; Brel, V.; Fournier, E.; Annereau, J. P.; Currie, E.; Guminski, Y.; Bonnet, D.; Bailly, C.; Guilbaud, N. F14512, a polyamine-vectorized anti-cancer drug, currently in clinical trials exhibits a marked preclinical anti-leukemic activity Leukemia 2013, 1-10
15. Wallick, C. J. G. I.; Thorne, M.; Feith, D. J.; Takasaki, K. Y.; Wilson, S. M.; Seki, J. A.; Pegg, A. E.; Byus, C. V.; Bachmann, A. S. Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitor-induced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells Oncogene 2005, 24, 5606-5618 (Pubitemid 43119354)
16. Meyskens, F. L., Jr.; Gerner, E. W. Development of Difluoromethylornithine (DFMO) as a chemoprevention agent Clin. Cancer Res. 1999, 5, 945-951 (Pubitemid 29233206)
17. Fabian, C. J.; Kimler, B. F.; Brady, D. A.; Mayo, M. S.; Chang, C. H.; Ferraro, J. A.; Zalles, C. M.; Stanton, A. L.; Masood, S.; Grizzle, W. E.; Boyd, N. F.; Arneson, D. W.; Johnson, K. A. A Phase II breast cancer chemoprevention trial of oral alpha-difluoromethylornithine: Breast tissue, imaging, and serum and urine biomarkers Clin. Cancer Res. 2002, 8, 3105-3117 (Pubitemid 35155020)
18. Abeloff, M. D.; Slavik, M.; Luk, G. D.; Griffin, C. A.; Hermann, J.; Blanc, O.; Sjoerdsma, A.; Baylin, S. B. Phase I trial and pharmacokinetic studies of alpha-difluoromethylornithine-an inhibitor of polyamine biosynthesis J. Clin. Oncol. 1984, 2, 124-130 (Pubitemid 14152455)
19. Ask, A.; Persson, L.; Heby, O. Increased survival of L1210 leukemic mice by prevention of the utilization of extracellular polyamines. Studies using a polyamine-uptake mutant, antibiotics and a polyamine-deficient diet Cancer Lett. 1992, 66 (1) 29-34
20. Chen, Y.; Weeks, R. S.; Burns, M. R.; Boorman, D. W.; Klein-Szanto, A. Combination therapy with 2-difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma Int. J. Cancer 2006, 118, 2344-2349
21. Burns, M. R.; Graminski, G. F.; Weeks, R. S.; Chen, Y.; O'Brien, T. G. Lipophilic lysine-spermine conjugates are potent polyamine transport inhibitors for use in combination with a polyamine biosynthesis inhibitor J. Med. Chem. 2009, 52, 1983-1993
22. Skorupskil, K. A.; O'Brien, T. G.; Guerrero, T.; Rodriguez, C. O.; Burns, M. R. Phase I/II clinical trials of 2-difluoromethylornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma Vet. Comp. Oncol. 2011, 9, 275-282
23. Igarashi, K.; Kashiwagi, K. Polyamine transport in bacteria and yeast Biochem. J. 1999, 344, 633-642 (Pubitemid 30032511)
24. 5B-type CATP-5 operates in polyamine transport and is crucial for norspermidine-mediated suppression of RNA interference FASEB J. 2010, 24, 206-217
25. de Tezanos Pinto, F.; Corradi, G. R.; de la Hera, D. P.; Adamo, H. P. CHO cells expressing the human P(5)-ATPase ATP13A2 are more sensitive to the toxic effects of herbicide paraquat Neurochem. Int. 2012, 60 (3) 243-248
26. Sala-Rabanal, M.; Li, D. C.; Dake, G. R.; Kurata, H. T.; Inyushin, M.; Skatchkov, S. N.; Nichols, C. G. Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3 Mol. Pharm. 2013, 10 (4) 1450-1458
27. Aouida, M.; Poulin, R.; Ramotar, D. The human carnitine transporter SLC22A16 mediates high affinity uptake of the anticancer polyamine analogue bleomycin-A5 J. Biol. Chem. 2010, 285 (9) 6275-6284
28. Uemura, T.; Stringer, D. E.; Blohm-Mangone, K. A.; Gerner, E. W. Polyamine transport is mediated by both endocytic and solute carrier transport mechanisms in the gastrointestinal tract Am. J. Physiol.: Gastrointest. Liver Physiol. 2010, 299 (2) G517-G522
29. Poulin, R.; Casero, R. A.; Soulet, D. Recent advances in the molecular biology of metazoan polyamine transport Amino Acids 2012, 42, 711-723
30. Soulet, D. C. L.; Kaouass, M.; Charest-Gaudreault, R.; Audette, M.; Poulin, R. Role of endocytosis in the internalization of spermidine-C(2)-BODIPY, a highly fluorescent probe of polyamine transport Biochem. J. 2002, 367, 347-357 (Pubitemid 35216809)
31. Soulet, D.; Gagnon, B.; Rivest, S.; Audette, M.; Poulin, R. A fluorescent probe of polyamine transport accumulates into intracellular acidic vesicles via a two-step mechanism J. Biol. Chem. 2004, 279, 49355-49366 (Pubitemid 39642166)
32. Belting, M.; Persson, S.; Fransson, L.-A. Proteoglycan involvement in polyamine uptake Biochem. J. 1999, 338, 317-323
33. Belting, M.; Mani, K.; Jonsson, M.; Cheng, F.; Sandgren, S.; Jonsson, S.; Ding, K.; Delcros, J.-G.; Fransson, L.-A. Glypican-1 is a vehicle for polyamine uptake in mammalian cells: A pivotal role for nirosothiol-derived nitric oxide J. Biol. Chem. 2003, 278, 47181-47189 (Pubitemid 37455394)
34. Bergeron, R. J.; McManis, J. S.; Weimar, W. R.; Schreier, K.; Gao, F.; Wu, Q.; Ortiz-Ocasio, J.; Luchetta, G.; Porter, C.; Vinson, J. R. The role of charge in polyamine analogue recognition J. Med. Chem. 1995, 38, 2278-2285
35. Phanstiel, O., IV; Kaur, N.; Delcros, J.-G. Structure-activity investigations of polyamine-anthracene conjugates and their uptake via the polyamine transporter Amino Acids 2007, 33, 305-313 (Pubitemid 47222973)
36. Kaur, N.; Delcros, J.-G.; Imran, J.; Khaled, A.; Chehtane, M.; Tschammer, N.; Martin, B.; Phanstiel, O., IV. A comparison of chloroambucil- and xylene-containing polyamines leads to improved ligands for accessing the polyamine transport system J. Med. Chem. 2008, 51, 1393-1401 (Pubitemid 351480400)
37. Phanstiel, O.; Archer, J. J. Design of polyamine transport inhibitors as therapeutics. In Polyamine Drug Discovery, 1st ed.; Casero, R. W. P., Ed.; Royal Society of Chemistry: London, 2011; p 302.
38. Burns, M. R.; Carlson, C. L.; Vanderwerf, S. M.; Ziemer, J. R.; Weeks, R. S.; Cai, F.; Webb, H. K.; Graminski, G. F. Amino acid/spermine conjugates: Polyamine amides as potent spermidine uptake inhibitors J. Med. Chem. 2001, 44, 3632-3644 (Pubitemid 33026671)
39. Gardner, R. A.; Kinkade, R.; Wang, C.; Phanstiel, O., IV. Total synthesis of petrobactin and its homologues as potential growth stimuli for Marinobacter hydrocarbonclasticus, an oil-degrading bacteria J. Org. Chem. 2004, 69, 3530-3537 (Pubitemid 38621303)
40. Kaur, N.; Delcros, J.-G.; Archer, J.; Weagraff, N. Z.; Martin, B.; Phanstiel, O., IV. Designing the polyamine pharmacophore: Influence of N-substituents on the transport behavior of polyamine conjugates J. Med. Chem. 2008, 51, 2551-2560 (Pubitemid 351628517)
41. Muth, A.; Kamel, J.; Kaur, N.; Shicora, A. C.; Ayene, I. S.; Gilmour, S. K.; Phanstiel, O., IV. Development of Polyamine Transport Ligands with Improved Metabolic Stability and Selectivity against Specific Human Cancers J. Med. Chem. 2013, 56, 5819-5828
42. Khomutov, A. R.; Shvetsov, A. S.; Vepsalainen, J. J.; Kritzyn, A. M. Novel acid-free cleavage of N -(2-hydroxyarylidene) protected amines Tetrahedron Lett. 2001, 42, 2887-2889 (Pubitemid 32250197)
43. Corce, V.; Morin, E.; Guiheneuf, S.; Renault, E.; Renaud, S.; Cannie, I.; Tripier, R.; Lima, L. M.; Julienne, K.; Gouin, S. G.; Loreal, O.; Deniaud, D.; Gaboriau, F. Polyaminoquinoline iron chelators for vectorization of antiproliferative agents: Design, synthesis, and validation Bioconjugate Chem. 2012, 23 (9) 1952-1968
44. Van Arman, S. A. 2-Methyl-2-propanol as a solvent for o -iodobenzoic acid (IBX) oxidation of 1 alcohols to aldehydes Tetrahedron Lett. 2009, 50, 4693-4695
45. Delcros, J.-G.; Tomasi, S.; Carrington, S.; Martin, B.; Renault, J.; Blagbrough, I. S.; Uriac, P. Effect of spermine conjugation on the cytotoxicity and cellular transport of acridine J. Med. Chem. 2002, 45, 5098-5111 (Pubitemid 35278706)
46. Mandel, J. L.; Flintoff, W. F. Isolation of mutant mammalian cells altered in polyamine transport J. Cell. Physiol. 1978, 97, 335-344
47. Byers, T. L.; Wechter, R.; Nuttall, M. E.; Pegg, A. E. Expression of a human gene for polyamine transport in chinese hamster ovary cells Biochem. J. 1989, 263, 745-752 (Pubitemid 19276453)
48. Weeks, R. S.; Vanderwerf, S. M.; Carlson, C. L.; Burns, M. R.; O'Day, C. L.; Cai, F.; Devens, B. H.; Webb, H. K. Novel lysine-spermine conjugate inhibits polyamine transport and inhibits cell growth when given with DFMO Exp. Cell Res. 2000, 261, 293-302
49. Heaton, M. A.; Flintoff, W. F. Methylglyoxal-bis(guanylhydrazone)- Resistant Chinese Hamster Ovary Cells: Genetic Evidence That More Than A Single Locus Controls Uptake J. Cell. Physiol. 1988, 136, 133-139
50. Frydman, B. J.; Marton, L. J.; Reddy, V. K.; Valasinas, A. L.; Witiak, D. T. Conformationally Restricted Polyamines. U.S. Patent 5,889,061, March 30, 1999.
51. Phanstiel, O.; Archer, J. J. Polyamine Transport Inhibitors as Novel Therapeutics. WO 2010/148390 A2, 2010.
52. American Cancer Society. Cancer Facts & Figures 2013; American Cancer Society: Atlanta, 2013; p 25.
53. Bruns, C. J.; Harbison, M. T.; Kuniyasu, H.; Eue, I.; Fidler, I. J. In vivo selection and characterization of metastatic variants from human pancreatic adenocarcinoma by using orthotopic implantation in nude mice Neoplasia 1999, 1 (1) 50-62
54. Basuroy, U. K.; Gerner, E. W. Emerging concepts in targeting the polyamine metabolic pathway in epithelial cancer chemoprevention and chemotherapy J. Biochem. 2006, 139, 27-33 (Pubitemid 43258843)
55. Azmi, A. S.; Ahmad, A.; Banerjee, S.; Rangnekar, V. M.; Mohammad, R. M.; Sarkar, F. H. Chemoprevention of pancreatic cancer: Characterization of Par-4 and its modulation by 3,3′ diindolylmethane (DIM) Pharm. Res. 2008, 25, 2117-2124
56. Grossie, V. B., Jr.; Ota, D. M.; Ajani, J. A.; Nishioka, K. Effect of intravenous alpha-difluoromethylornithine on the polyamine levels of normal tissue and a transplantable fibrosarcoma Cancer Res. 1987, 47 (7) 1836-1840 (Pubitemid 17056686)
57. Casero, R. A., Jr.; Marton, L. J. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases Nat. Rev. Drug Discovery 2007, 6 (5) 373-390 (Pubitemid 46705201)
58. Nilsson, B. O.; Kockum, I.; Rosengren, E. Inhibition of diamine oxidase promotes uptake of putrescine from rat small intestine Inflammation Res. 1996, 45 (10) 513-518 (Pubitemid 26360011)
59. Holtta, E.; Pulkkinen, P.; Elfving, K.; Janne, J. Oxidation of polymines by diamine oxidase from human seminal plasma Biochem. J. 1975, 145 (2) 373-378
60. Gahl, W. A.; Pitot, H. C. Reversal by aminoguanidine of the inhibition of proliferation of human fibroblasts by spermidine and spermine Chem.-Biol. Interact. 1978, 22 (1) 91-98 (Pubitemid 8406481)
61. Morgan, D. M. Polyamine oxidases and oxidized polyamines. In Physiology of Polyamines; Bachrach, U.; Heimer, Y. M., Eds.; CRC Press: Boca Raton, FL, 1989; Vol. 1, pp 203-229.
62. Bergeron, R. J.; Feng, Y.; Weimar, W. R.; McManis, J. S.; Dimova, H.; Porter, C.; Raisler, B.; Phanstiel, O. A comparison of structure-activity relationships between spermidine and spermine analogue antineoplastics J. Med. Chem. 1997, 40, 1475-1494 (Pubitemid 27200764)
63. Kurihara, S.; Sakai, Y.; Suzuki, H.; Muth, A.; Phanstiel, O., IV; Rather, P. N. Putrescine importer PlaP contributes to swarming motility and urothelial cell invasion in Proteus mirabilis J. Biol. Chem. 2013, 288 (22) 15668-15676
64. Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxic assays J. Immunol. Methods 1983, 65, 55-63 (Pubitemid 14203433)
65. Minocha, S. C.; Minocha, R.; Robie, C. A. High-performance liquid chromatographic method for the determination of dansyl-polyamines J. Chromatogr. 1990, 511, 177-183 (Pubitemid 20197931)
66. Gardner, R. A.; Belting, M.; Svensson, K.; Phanstiel, O., IV. Synthesis and transfection efficiencies of new lipophilic polyamines J. Med. Chem. 2007, 50, 308-318 (Pubitemid 46151065)
67. Geall, A. J.; Blagbrough, I. S. Homologation of polyamines in the synthesis of lipo-spermine conjugates and related lipoplexes Tetrahedron Lett. 1998, 39, 443-446 (Pubitemid 28018269)