Structure-activity relationship (SAR) study of ethyl 2-amino-6-(3,5- dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) and the potential of the lead against multidrug resistance in cancer treatment

Journal of Medicinal Chemistry

Volumn 55, Issue 11, 2012, Pages 5566-5581

  Aridoss, Gopalakrishnan ^a   Zhou, Bo ^a   Hermanson, David L ^a   Bleeker, Nicholas P ^a   Xing, Chengguo ^a  

^a UNIVERSITY OF MINNESOTA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CAMPTOTHECIN; CARBOXYLIC ACID DERIVATIVE; CHROMENE DERIVATIVE; CXL017; DAUNORUBICIN; DOXORUBICIN; ETHYL 2 [2 AMINO 3 CYANO 6 (3,5 DIMETHOXYPHENYL) 4H CHROMEN 4 YL]ACETATE; ETHYL 2 [2 AMINO 6 (3,5 DIMETHOXYPHENYL)]3 [[3 (4 METHOXYPHENYL) 1,2,4 OXADIAZOL 5 YL] 4H CHROMEN 4 YL]ACETATE; ETHYL 2 AMINO 4 (2 ETHOXY 2 OXOETHYL) 6 (2 FLUOROPHENYL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 4 (2 ETHOXY 2 OXOETHYL) 6 (2 METHOXYPYRIDIN 4 YL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 4 (2 ETHOXY 2 OXOETHYL) 6 (3 FLUOROPHENYL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 4 (2 ETHOXY 2 OXOETHYL) 6 (4 FLUOROPHENYL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 4 (2 ETHOXY 2 OXOETHYL) 6 (FURAN 2 YL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 4 (2 ETHOXY 2 OXOETHYL) 6 (PYRIDIN 2 YL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 4 (2 ETHOXY 2 OXOETHYL) 6 (PYRIDIN 3 YL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 4 (2 ETHOXY 2 OXOETHYL) 6 (PYRIMIDIN 3,5 YL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 4 (2 ETHOXY 2 OXOETHYL) 6 (THIOPHEN 2 YL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 6 (2,4 DIFLUOROPHENYL) 4 (2 ETHOXY 2 OXOETHYL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 6 (3 AMINOPHENYL) 4 (2 ETHOXY 2 OXOETHYL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 6 (3 AMINOPHENYL) 4 [2 OXO 2 (PROP 2 YN 1 YLOXY)ETHYL] 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 6 (3,5 DIFLUOROPHENYL) 4 (2 ETHOXY 2 OXOETHYL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 6 (3,5 DIMETHOXYPHENYL) 4 (2 ETHOXY 2 OXOETHYL) 4H CHROMENE 3 CARBOXYLATE; ETHYL 2 AMINO 6 BROMO 4 (2 ETHOXY 2 OXOETHYL) 4H CHROMENE 3 CARBOXYLATE; HOMOHARRINGTONINE; METHYL 2 AMINO 6 (3,5 DIMETHOXYPHENYL) 4 (2 ETHOXY 2 OXOETHYL) 4G CHROMENE 3 CARBOXYLATE; METHYL 2 AMINO 6 (3,5 DIMETHOXYPHENYL) 4 (2 METHOXY 2 OXOETHYL) 4H CHROMENE 3 CARBOXYLATE; MITOXANTRONE; OXADIAZOLE DERIVATIVE; OXIRAN 2 YLMETHYL 2 AMINO 6 (3,5 DIMETHOXYPHENYL) 4 [2 (OXIRAN 2 YLMETHOXY) 2 OXOETHYL] 4H CHROMENE 3 CARBOXYLATE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VINBLASTINE;

ARTICLE; CANCER CELL CULTURE; CANCER RESISTANCE; CANCER THERAPY; CELL STRAIN HL 60; CYCLIZATION; DRUG CYTOTOXICITY; DRUG POTENCY; DRUG PURIFICATION; DRUG SENSITIVITY; HYDROPHILICITY; HYDROPHOBICITY; IC 50; IN VITRO STUDY; MULTIDRUG RESISTANCE; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION;

ANTINEOPLASTIC AGENTS; BENZOPYRANS; CELL LINE, TUMOR; DRUG RESISTANCE, MULTIPLE; DRUG RESISTANCE, NEOPLASM; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; P-GLYCOPROTEIN; PROTO-ONCOGENE PROTEINS C-BCL-2; SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84862271660     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300515q     Document Type: Article

References (50)

1. Reed, J. C.; Pellecchia, M. Apoptosis-based therapies for hematologic malignancies Blood 2005, 106, 408-418
2. Glenda, G.; Rubin, M.; Gail, W.; Ihor, S.; Ralph, B. Apoptosis and expression of Bcl-2, Bcl-XL, and Bax in renal cell carcinomas Cancer Invest. 2002, 20, 324-332
3. Sartorious, U. A.; Krammer, P. H. Upregulation of Bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines Int. J. Cancer 2002, 97, 584-592
4. Gottesman, M. M.; Ludwig, J.; Xia, D.; Szakacs, G. Defeating drug resistance in cancer Discovery Med 2006, 6, 18-23
5. Szakacs, G.; Paterson, J. K.; Ludwig, J. A.; Booth-Genthe, C.; Gottesman, M. M. Targeting multidrug resistance in cancer Nat. Rev. Drug Discovery 2006, 5, 219-234
6. Youle, R. J.; Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death Nat. Rev. Mol. Cell Biol. 2008, 9, 47-59
7. Segezdi, E.; Macdonald, D. C.; Ni Chonghaile, T.; Gupta, S.; Samali, A. Bcl-2 family on guard at the ER Am. J. Physiol.: Cell Physiol. 2009, 296, C941-953
8. Distelhorst, C. W.; Shore, G. C. Bcl-2 and calcium: controversy beneath the surface Oncogene 2004, 23, 2875-2880
9. Chen, R.; Valencia, I.; Zhong, F.; McColl, K. S.; Roderick, H. L.; Bootman, M. D.; Berridge, M. J.; Conway, S. J.; Holmes, A. B.; Mignery, G. A.; Velez, P.; Distelhorst, C. W. Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate J. Cell Biol. 2004, 166, 193-203
10. 2+ release through inositol 1,4,5-trisphosphate receptors and inhibits Ca(2+) uptake by mitochondria without affecting ER calcium store content Cell Calcium 2008, 44, 324-338
11. Li, C.; Wang, X.; Vais, H.; Thompson, C. B.; Foskett, J. K.; White, C. Apoptosis regulation by Bcl-x(L) modulation of mammalian inositol 1,4,5-trisphosphate receptor channel isoform gating Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 12565-12570
12. Kuo, T. H.; Kim, H. R.; Zhu, L.; Yu, Y.; Lin, H. M.; Tsang, W. Modulation of endoplasmic reticulum calcium pump by Bcl-2 Oncogene 1998, 17, 1903-1910
13. Dremina, E. S.; Sharov, V. S.; Schöneich, C. Displacement of SERCA from SR lipid caveolae-related domains by Bcl-2: a possible mechanism for SERCA inactivation Biochemistry 2006, 45, 175-184
14. Grabowski, D. R.; Dubyak, G. R.; Rybicki, L.; Hidaka, H.; Ganapathi, R. Tumor cell resistance to topoisomerase II poisons: role for intracellular free calcium in the sensitization by inhibitors or calcium-calmodulin-dependent enzymes Biochem. Pharmacol. 1998, 56, 345-349
15. Tombal, B.; Weeraratna, A. T.; Denmeade, S. R.; Isaacs, J. T. Thapsigargin induces a calmodulin/calcineurin-dependent apoptotic cascade responsible for the death of prostatic cancer cells Prostate 2000, 43, 303-317
16. Morjani, H.; Madoulet, C. Immunosuppressors as multidrug resistance reversal agents Methods Mol. Biol. 2010, 596, 433-446
17. Oltersdorf, T.; Elmore, S. W.; Shoemaker, A. R.; Armstrong, R. C.; Augeri, D. J.; Belli, B. A.; Bruncko, M.; Deckwerth, T. L.; Dinges, J.; Hajduk, P. J.; Joseph, M. K.; Kitada, S.; Korsmeyer, S. J.; Kunzer, A. R.; Letai, A.; Li, C.; Mitten, M. J.; Nettesheim, D. J.; Ng, S.; Nimmer, P. M.; O'Connor, J. M.; Oleksijew, A.; Petros, A. M.; Reed, J. C.; Shen, W.; Tahir, S. K.; Thompson, C. B.; Tomaselli, K. J.; Wang, B.; Wendt, M. B.; Zhang, H.; Fesik, S. W.; Rosenberg, S. H. An inhibitor of Bcl-2 family proteins induces regression of solid tumours Nature 2005, 435, 677-681
18. Roberts, A. W.; Seymour, J. F.; Brown, J. R.; Wierda, W. G.; Kipps, T. J.; Khaw, S. L.; Carney, D. A.; He, S. Z.; Huang, D. C.; Xiong, H.; Cui, Y.; Busman, T. A.; McKeegan, E. M.; Krivoshik, A. P.; Enschede, S. H.; Humerickhouse, R. Substantial susceptibility of chronic lymphocytic leukemia to Bcl2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease J. Clin. Oncol. 2012, 30, 488-496
19. Wong, M.; Tan, N.; Zha, J.; Peale, F. V.; Yue, P.; Fairbrother, W. J.; Belmont, L. D. Navitoclax (ABT-263) reduces Bcl-xL mediated chemo-resistance in ovarian cancer models Mol. Cancer Ther. 2012, 11, 1017-1025
20. L family inhibitor ABT-737 sensitizes ovarian cancer cells to carboplatin Clin. Cancer Res. 2007, 13, 7191-7198
21. Hall, M. D.; Brimacombe, K. R.; Varonka, M. S.; Pluchino, K. M.; Monda, J. K.; Li, J.; Walsh, M. J.; Boxer, M. B.; Warren, T. H.; Fales, H. M.; Gottesman, M. M. Synthesis and structure-activity evaluation of isatin-beta-thiosemicarbazones with improved selective activity toward multidrug-resistant cells expressing P-glycoprotein J. Med. Chem. 2011, 54, 5878-5889
22. Hall, M. D.; Handley, M. D.; Gottesman, M. M. Is resistance useless? Multidrug resistance and collateral sensitivity Trends. Pharmacol. Sci. 2009, 30, 546-556
23. Wang, J.; Liu, D.; Zhang, Z.; Shan, S.; Han, X.; Srinivasula, S. M.; Croce, C. M.; Alnemri, E. S.; Huang, Z. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7124-7129
24. Lickliter, J. D.; Wood, N. J.; Johnson, L.; McHugh, G.; Tan, J.; Wood, F.; Cox, J.; Wickham, N. W. HA14-1 selectively induces apoptosis in Bcl-2-overexpressing leukemia/lymphoma cells, and enhances cytarabine-induced cell death Leukemia 2003, 17, 2074-2080
25. An, J.; Chen, C.; Huang, Z. Critical upstream signals of cytochrome c release induced by a novel Bcl-2 inhibitor J. Biol. Chem. 2004, 279, 19133-19140
26. Doshi, J. M.; Xing, C. Antagonists against anti-apoptotic Bcl-2 family proteins for cancer treatment Mini-Rev. Org. Chem. 2008, 5, 171-178
27. Doshi, J. M.; Tian, D.; Xing, C. Ethyl-2-amino-6-bromo-4-(1-cyano-2- ethoxy-2-oxoethyl)-4 H -chromene-3-carboxylate (HA 14-1), a prototype small-molecule antagonist against anti-apoptotic Bcl-2 proteins, decomposes to generate reactive oxygen species (ROS) that induce apoptosis Mol. Pharmaceutics 2007, 4, 919-928
28. Tian, D.; Das, S.; Doshi, J. M.; Peng, J.; Lin, J.; Xing, C. sHA 14-1, a stable and ROS-free antagonist against anti-apoptotic Bcl-2 proteins, bypasses drug resistances and synergizes cancer therapies in human leukemia cell Cancer Lett. 2008, 259, 198-208
29. Das, S. G.; Doshi, J. M.; Tian, D.; Addo, S. N.; Srinivasan, B.; Hermanson, D.; Xing, C. Structure activity relationships and molecular mechanisms of sHA 14-1 and its analogs J. Med. Chem. 2009, 52, 5937-5949
30. Das, S. G.; Srinivasan, B.; Hermanson, D. L.; Bleeker, N.; Doshi, J. M.; Tang, R.; Beck, W. T.; Xing, C. Structure activity relationship and molecular mechanisms of ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4 H -chromene-3-carboxylate (CXL017) and its analogs J. Med. Chem. 2011, 54, 5937-5948
31. Hermanson, D.; Addo, S. N.; Bajer, A. A.; Marchant, J. S.; Das, S. G. K.; Srinivasan, B.; Al-Mousa, F.; Michelangeli, F.; Thomas, D. D.; LeBien, T. W.; Xing, C. Dual mechanisms of sHA 14-1 in inducing cell death through endoplasmic reticulum and mitochondria Mol. Pharmacol. 2009, 76, 667-678
32. Starcevic, S.; Brozic, P.; Turk, S.; Cesar, J.; Rizner, T. L.; Gobec, S. Synthesis and biological evaluation of (6- and 7-phenyl) coumarin derivatives as selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 J. Med. Chem. 2011, 54, 248-261
33. Liu, K. C.; Shelton, B. R.; Howe, R. K. A particularly convenient preparation of benzohydroximinoyl chlorides, nitrile oxide precursors J. Org. Chem. 1980, 45, 3916-3918
34. Kumar, R. R.; Perumal, S.; Menendez, J. C.; Yogeeswari, P.; Sriram, D. Antimycobacterial activity of novel 1,2,4-oxadiazole-pyranopyridine/chromene hybrids generated by chemoselective 1,3-dipolar cycloadditions of nitrile oxides Bioorg. Med. Chem. 2011, 19, 3444-3450
35. Knapp, D. M.; Gillis, E. P.; Burke, M. D. A general solution for unstable boronic acids: slow-release cross-coupling from air-stable MIDA boronates J. Am. Chem. Soc. 2009, 131, 6961-6963
36. Curini, M.; Rosati, O.; Marcotullio, M. C.; Montanari, F.; Campagna, V.; Pace, V.; Cravotto, G. Preparation of 2-amino-4 H -chromene derivatives from coumarins in basic media Eur. J. Org. Chem. 2006, 746-751
37. Ramesh, D.; Srinivasan, M. Studies on ring opening of coumarins Curr. Sci. 1984, 53, 369-371
38. Bhanu Prasad, B. A.; Gilbertson, S. R. One-pot synthesis of N-heterocyclic carbene ligands from a N -(2-iodoethyl)arylamine salts Org. Lett. 2009, 11, 3710-3713
39. 3H)][OTf] Eur. J. Org. Chem. 2011, 2827-2835
40. Vaziri, S. A.; Grabowski, D. R.; Tabata, M.; Holmes, K. A.; Sterk, J.; Takigawa, N.; Bukowski, R. M.; Ganapathi, M. K.; Ganapathi, R. c-IAP1 is overexpressed in HL-60 cells selected for doxorubicin resistance: effects on etoposide-induced apoptosis Anticancer Res. 2003, 23, 3657-3661
41. Harker, W. G.; Slade, D. L.; Drake, F. H.; Parr, R. L. Mitoxantrone resistance in HL-60 leukemia cells: reduced nuclear topoisomerase II catalytic activity and drug-induced DNA cleavage in association with reduced expression of the topoisomerase II beta isoform Biochemistry 1991, 30, 9953-9961
42. Harker, W. G.; Slade, D. L.; Dalton, W. S.; Meltzer, P. S.; Trent, J. M. Multidrug resistance in mitoxantrone-selected HL-60 leukemia cells in the absence of P-glycoprotein overexpression Cancer Res. 1989, 49, 4542-4549
43. Fujimori, A.; Harker, W. G.; Kohlhagen, G.; Hoki, Y.; Pommier, Y. Mutation at the catalytic site of topoisomerase I in CEM/C2, a human leukemia cell line resistant to camptothecin Cancer Res. 1995, 55, 1339-1346
44. Fujimori, A.; Hoki, Y.; Popescu, N. C.; Pommier, Y. Silencing and selective methylation of the normal topoisomerase I gene in camptothecin- resistant CEM/C2 human leukemia cells Oncol. Res. 1996, 8, 295-301
45. Chen, M.; Beck, W. T. DNA topoisomerase II expression, stability, and phosphorylation in two VM-26-resistant human leukemic CEM sublines Oncol. Res. 1995, 7, 103-111
46. Beck, W. T.; Mueller, T. J.; Tanzer, L. R. Altered surface membrane glycoproteins in vinca alkaloid-resistant human leukemic lymphoblasts Cancer Res. 1979, 39, 2070-2076
47. Tang, R.; Cohen, S.; Perrot, J. Y.; Faussat, A. M.; Zuany-Amorim, C.; Marjanovic, Z.; Morjani, H.; Fava, F.; Corre, E.; Legrand, O.; Marie, J. P. P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients BMC Cancer 2009, 9, 199
48. Cai, J.; Damaraju, V. L.; Groulx, N.; Mowles, D.; Peng, Y.; Robins, M. J.; Cass, C. E.; Gros, P. Two distinct molecular mechanisms underlying cytarabine resistance in human leukemic cells Cancer Res. 2008, 68, 2349-2357
49. Denmeade, S. R.; Jakobsen, C. M.; Janssen, S.; Khan, S. R.; Garrett, E. S.; Lilja, H.; Christensen, S. B.; Isaacs, J. T. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer J. Natl. Cancer Inst. 2003, 95, 990-1000
50. Kapoor, R.; Slade, D. L.; Fujimori, A.; Pommier, Y.; Harker, W. G. Altered topoisomerase I expression in two subclones of human CEM leukemia selected for resistance to camptothecin Oncol. Res. 1995, 7, 83-95