Single agents with designed combination chemotherapy potential: Synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents

Journal of Medicinal Chemistry

Volumn 53, Issue 4, 2010, Pages 1563-1578

  Gangjee, Aleein ^a   Zaware, Nilesh ^a   Raghavan, Sudhir ^a   Ihnat, Michael ^b   Shenoy, Satyendra ^b   Kisliuk, Roy L ^c  

^a DUQUESNE UNIVERSITY   (United States)

^b UNIVERSITY OF OKLAHOMA COLLEGE OF MEDICINE   (United States)

^c TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINO 5 CHLORO 3,9 DIHYDRO 4H PYRIMIDO[4,5 B]INDOL 4 ONE; 5 [(4 METHYLPHENYL)THIO] 9H PYRIMIDO[4,5 B]INDOLE 2,4 DIAMINE; 5 CHLORO 9H PYRIMIDO[4,5 B]INDOLE 2,4 DIAMINE; 5 CHLORO 9H PYRIMIDO[4,5 B]INDOLE 2,4 DIAMINE PROPANAMIDE; 5 PHENYLTHIO 9H PYRIMIDO[4,5 B]INDOLE 2,4 DIAMINE; ANTINEOPLASTIC AGENT; DIHYDROFOLATE REDUCTASE; ETHYL 2 AMINO 4 CHLORO 1H INDOLE 3 CARBOXYLATE; N (4,5 DICHLORO 9H PYRIMIDO[4,5 B]INDOL 2 YL) 2,2 DIMETHYLPROPANAMIDE; N (5 CHLORO 4 OXO 4,9 DIHYDRO 3H PYRIMIDO[4,5 B]INDOL 2 YL) 2,2 DIMETHYLPROPANAMIDE; PLATELET DERIVED GROWTH FACTOR BETA RECEPTOR; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; PYRIMIDO[4,5 B]INDOLE DERIVATIVE; THIOPHENOL DERIVATIVE; THYMIDYLATE SYNTHASE; THYMIDYLATE SYNTHASE INHIBITOR; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR 2;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIANGIOGENIC ACTIVITY; ARTICLE; BLOOD VESSEL; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CELL VIABILITY; CONTROLLED STUDY; CYTOTOXICITY; DRUG ACTIVITY; DRUG DESIGN; DRUG SCREENING; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; IC 50; LIVER METASTASIS; MALE; MOUSE; NONHUMAN; SUBSTITUTION REACTION; X RAY CRYSTALLOGRAPHY;

ANGIOGENESIS INHIBITORS; ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; CHICK EMBRYO; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; INDOLES; MALE; MICE; MICE, NUDE; MODELS, MOLECULAR; NEOPLASM TRANSPLANTATION; PYRIMIDINES; RECEPTOR, PLATELET-DERIVED GROWTH FACTOR BETA; STRUCTURE-ACTIVITY RELATIONSHIP; SULFHYDRYL COMPOUNDS; THYMIDYLATE SYNTHASE; TRANSPLANTATION, HETEROLOGOUS; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 77649207346     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm9011142     Document Type: Article

References (135)

1. Davis, D. W.; Herbst, R. S.; Abbruzzese, J. L. Antiangiogenic Cancer Therapy; CRC Press, Taylor and Francis Group: Boca Raton, FL: 2008; p 841.
2. Folkman, J. Angiogenesis. Annu. Rev. Med. 2006, 57, 1-18.
3. Fabbro, D., McCormick, F., Eds. Protein Tyrosine Kinases: From Inhibitors to Useful Drugs; Humana Press, Totowa, NJ, 2006; 290 pp.
4. Gschwind, A.; Fischer, O. M.; Ullrich, A. Timeline: The discovery of receptor tyrosine kinases: Targets for cancer therapy. Nat. Rev. Cancer 2004, 4, 361-370.
5. Carmeliet, P.; Jain, R. K. Angiogenesis in cancer and other diseases. Nature 2000, 407, 249-257.
6. Gorre, M.E.;Mohammed, M.; Ellwood, K.; Hsu, N.; Paquette, R.; Rao, P. N.; Sawyers, C. L. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001, 293, 876-880.
7. Gorre, M. E.; Sawyers, C. L. Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia. Curr. Opin. Hematol. 2002, 9, 303-307.
8. Hurwitz, H.; Fehrenbacher, L.; Novotny, W.; Cartwright, T.; Hainsworth, J.; Heim, W.; Berlin, J.; Baron, A.; Griffing, S.; Holmgren, E.; Ferrara, N.; Fyfe, G.; Rogers, B.; Ross, R.; Kabbinavar, F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 2004, 350, 2335-2342.
9. Oestman, A. PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev. 2004, 15, 275-286.
10. Pearson, M.; Garcia-Echeverria, C.; Fabbro, D. Protein Tyrosine Kinases as Targets for Cancer and Other Indications in Protein Tyrosine Kinases. In From Inhibitors to Useful Drugs; Fabbro, D., McCormick, F., Eds.; Human Press, Totowa, NJ, 2005, pp 1-29.
11. Stein, M. N.; Flaherty, K. T. CCR drug updates: Sorafenib and sunitinib in renal cell carcinoma. Clin. Cancer Res. 2007, 13, 3765-3770.
12. Tabernero, J. The role of VEGF and EGFR inhibition: Implications for combining anti-VEGF and anti-EGFR agents. Mol. Cancer Res. 2007, 5, 203-220.
13. Jain, R. K.; Duda, D. G.; Clark, J. W.; Loeffler, J. S. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat. Clin. Pract. Oncol. 2006, 3, 24-40.
14. Slamon, D. J.; Leyland-Jones, B.; Shak, S.; Fuchs, H.; Paton, V.; Bajamonde, A.; Fleming, T.; Eiermann, W.; Wolter, J.; Pegram, M.; Baselga, J.; Norton, L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 2001, 344, 783-792.
15. Bergers, G.; Song, S.; Meyer-Morse, N.; Bergsland, E.; Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 2003, 111, 1287-1295.
16. Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 2005, 438, 932-936.
17. Gasparini, G.; Longo, R.; Fanelli, M.; Teicher, B. A. Combination of antiangiogenic therapy with other anticancer therapies: Results, challenges, and open questions. J. Clin. Oncol. 2005, 23, 1295-1311.
18. Casanovas, O.; Hicklin, D. J.; Bergers, G.; Hanahan, D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005, 8, 299-309. (Pubitemid 41443415)
19. Mancuso, M. R.; Davis, R.; Norberg, S. M.; O'Brien, S.; Sennino, B.; Nakahara, T.; Yao, V. J.; Inai, T.; Brooks, P.; Freimark, B.; Shalinsky, D. R.; Hu-Lowe, D. D.; McDonald, D. M. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J. Clin. Invest. 2006, 116, 2610-2621.
20. Ma, J.; Waxman, D. J. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Mol. Cancer Ther. 2008, 7, 3670-3684.
21. Gangjee, A.; Zeng, Y.; Ihnat, M.; Warnke, L. A.; Green, D. W.; Kisliuk, R. L.; Lin, F.-T. Novel 5-substituted, 2,4-diaminofuro-[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors with antiangiogenic and antitumor activity. Bioorg. Med. Chem. 2005, 13, 5475-5491.
22. Fukumura, D.; Jain, R. K. Tumor microvasculature and microenvironment: Targets for anti-angiogenesis and normalization. Microvasc. Res. 2007, 74, 72-84.
23. Browder, T.; Butterfield, C. E.; Kraling, B. M.; Shi, B.; Marshall, B.; O'Reilly, M. S.; Folkman, J. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000, 60, 1878-1886. (Pubitemid 30207647)
24. Ferrara, N.; Kerbel, R. S. Angiogenesis as a therapeutic target. Nature 2005, 438, 967-974.
25. Klement, G.; Baruchel, S.; Rak, J.; Man, S.; Clark, K.; Hicklin, D. J.; Bohlen, P.; Kerbel, R. S. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 2000, 105, R15-R24.
26. Ho, Q. T.; Kuo, C. J. Vascular endothelial growth factor: Biology and therapeutic applications. Int. J. Biochem. Cell Biol. 2007, 39, 1349-1357.
27. Lindahl, P. J. B. R.; Levéen, P.; Betsholtz, C. Pericyte Loss and Microaneurysm Formation in PDGF-B-Deficient Mice. Science 1997, 277 (5323), 242-245.
28. Sjöblom, T. P., K.; Östman, A. Heldin, C.-H. Platelet-derived growth factor. Normal function, role in disease and application of PDGF antagonists. In Protein Tyrosine Kinases: From Inhibitors to Useful Drugs; Fabbra, D., McCormick, F., Eds.; Humana Press, Totowa, NJ, 2006; pp 161-186.
29. Clinical Trials: Combination of Capecitabine withKinase Inhibitors: Capecitabine (Xeloda) and Lapatinib (Tykerb) as First-line Therapy in HER2/Neu-positive Breast Cancer. http://www.clinicaltrials.gov/ct2/show/ NCT00496366?term=capecitabine&rank=4;
30. http://www. clinicaltrials.gov/ct2/show/NCT00496366?term= capecitabine&rank=4
31. ; A study of Sunitinib in Combination with Capecitabine Compared with Capecitabine in Patients with Breast Cancer, http://www.clinicaltrials.gov/ct2/ show/NCT00435409?term=capecitabine&rank=5;
32. Study of Sunitinib in Combination with Cisplatin/Capecitabine or Oxaliplatin/Capecitabine in PatientswithAdvancedGastricCancer, http://www.clinicaltrials.gov/ct2/show/NCT00555620?term=capecitabine&rank=6
33. ; Bevacizumab, Erlotinib and Capecitabine for Locally Advanced Rectal Cancer, http://www.clinicaltrials.gov/ct2/show/NCT00543842?term= capecitabine&rank=15;
34. Capecitabine/Erlotinib Followed of Gemcitabine Versus Gemcitabinie/Erlotnib Followed of Capecitabine, http://www.clinicaltrials.gov/ ct2/show/NCT00440167;
35. A Phase I Trial of Capecitabine in Combination with Gemcitabine and Erlotinib for Advanced Pancreatic Cancer, http://www.clinicaltrials.gov/ct2/ show/NCT00480584;
36. Gemcitabine/Vinorelbine versus Gemcitabine/Cisplatin versus Gemcitabine/Capecitabine in Metastatic Breast Cancer, http://www.clinicaltrials. gov/ct2/show/NCT00480597;
37. A Phase II Trial of Gemcitabine, Capecitabine and Bevacizumab in Metastatic Renal Cell Carcinoma, http://www.clinicaltrials.gov/ct2/show/ NCT0000523640;
38. BrainMets-Capecitabine and WBRT, http://www.clinicaltrials.gov/ct2/show/ NCT00570908?term=capecitabine&rank=19
39. ; Combination Study of Capecitabine and Erlotinib Concurrent with Radiotherapy for Nonoperable Advanced Pancreatic Cancer, http://www. clinicaltrials.gov/ct2/show/NCT00565487?term=capecitabine&rank=30;
40. Phase I Vandetanib Plau Capecitabine, Oxaliplatin and Bevacizumab for Metastatic Colorectal Cancer, http://www.clinicaltrials.gov/ct2/show/ NCT00532909?term=capecitabine&rank=44
41. ; Phase I Study of Lapatinib in combination with Oxaliplatin and Capecitabine in Sugjects with Advanced Colorectal Cancer, http://www. clinicaltrials.gov/ct2/show/NCT00536809?term=capecitabine&rank=74;
42. Enzastaurin in combination of Capecitabine to Treat Breat Cancer, http://www.clinicaltrials.gov/ct2/show/NCT00437294?term=capecitabine&rank= 92;
43. Imatinib Mesylate, Gemcitabine and Capecitabine in Treating Patients with Advanced Solid Tumors, http://www.clinicaltrials.gov/ct2/show/NCT00483366?term= capecitabine&rank=93;
44. Lapatinib A Capecitabine Treatment for Advanced Metastatic Breast Cancer in Women from China, http://www.clinicaltrials.gov/ct2/show/NCT00508274?term= capecitabine&rank=101;
45. A Clinical Trial Comparing Efficacy and Safety of Sunitinib and Capecitabine, http://www.clinicaltrials.gov/ct2/show/NCT00373113?term= capecitabine&rank=150;
46. Study for Patients with Untreated Gastric CancerWhoWill Receive Capecitabine and Lapatinib, http://www.clinicaltrials.gov/ct2/show/ NCT0000570908? term=capecitabine&rank=152;
47. EAP (Expanded Access Protocol) of Lapatinib Combinied with Capecitabine in Metastatic Breast Cancer, http://www.clinicaltrials.gov/ct2/show/NCT00338247? term=capecitabine&rank=167;
48. Phase I/II XP A Sorafenib in AGC, http://www.clinicaltrials.gov/ct2/show/ NCT00565370?term=capecitabine&rank=250.
49. A Brain Metastases in ErbB2-Positive Breast Cancer, http://www. clinicaltrials.gov/ct2/show/NCT00437073?term=capecitabine&rank=267;
50. Lapatinib in Combination with Capecitabine in Japanese Patients with Metastatic Breast Cancer, http://www.clinicaltrials.gov/ct2/show/NCT00477464? term=capecitabine&rank=309;
51. Clinical Trial on the Mixture of Gemcitabine, Capecitabine and Sorafenib (Bay 43-9006) in the Treatment of Patients with Renal Cell Carcinoma (RCC) (SOGUG-02-06), http://www.clinicaltrials.gov/ct2/show/NCT00496301?term= capecitabine&rank=311;
52. Erlotinib, Combination Chemotherapy and Radiation Therapy in Treating Patients with Stage I or Stage II Pancreatic Cancer that can be Removed by Surgery, http://www.clinicaltrials.gov/ct2/show/NCT00313560?term= capecitabine&rank=352.
53. Tripathy, D. Capecitabine in combination with novel targeted agents in the management of metastatic breast cancer: underlying rationale and results of clinical trials. Oncologist 2007, 12, 375-389. (Pubitemid 46698715)
54. Clinical Trials Combination of 5-FU with Kinase Inhibitors: Bevacizumab, Erlotinib and 5-Fluorouracil with External Beam Radiation Therapy in Locally Advanced Rectal Cancer,. http://www.clinicaltrials.gov/ct2/show/NCT00307736;
55. Study of Erlotinib and Chemotherapy for Unresectable or Metastatic Cancer of the Esophagus and Gastric Cardia, http://www.clinicaltrials.gov/ct2/show/ NCT00591123;
56. Sunitinib, Irinotecan, Fluorouracil and Leucovorini in Treating Patients with Advanced Stomach Cancer or Gastroesophageal Cancer, http://www. clinicaltrials.gov/ct2/show/NCT00524186;
57. A Phase I Study of Sunitinib in combina tion with Cisplatin and 5-Fluorouracil in Patients with Advanced Gastric Cancer, http://www. clinicaltrials.gov/ct2/show/NCT00555672;
58. Oxaliplatin, Fluorouracil, Erlotinib and Radiation Therapy before Surgery and Erlotinib After Sursery in Treating Patients with Locally Advanced Cancer of the Esophagus or Gastroesophageal Junction, http://www.clinicaltrials.gov/ ct2/show/NCT00499564;
59. Cisplatin, Fluorouracil, Gefitinib and Radiation Therapy in Treating Patients with Locally Advanced Head and Neck Cancer, http://www.clinicaltrials. gov/ct2/show/NCT00352105;
60. Study of FOLFIRI Chemotherapy with or without Sunitinib in Patients with Metastatic Colorectal Cancer, http://www.clinicaltrials.gov/ct2/show/ NCT00457691;
61. Docetaxel and Lapatinib with or without Combination Chemotherapy or Docetaxel and Trastuzumab with Combination Chemotherapy in Treating Women with Locally Advanced, Inflammatory or Resectable Breast Cancer, http://www. clinicaltrials.gov/ct2/show/NCT00450892;
62. Chemotherapy, Radiation Therapy and Immunotherapy Prior to Surgery in Operable Esophageal Cancer, http://www.clinicaltrials.gov/ct2/show/NCT00393068;
63. Combination Chemotherapy and Radiation therapy with or without Lapatinib in Treating Patients with Locally Advanced Cancer of the Larynx or Hypopharynx That Can Be Removed by Surgery, http://www.clinicaltrials.gov/ct2/show/ NCT00498953;
64. Lapatinib +/- Trastuzumab in addition to Standard Neoadjuvant Breast Cancer Therapy, http://www.clinicaltrials.gov/ct2/show/NCT00524303;
65. Chemotherapy & Erlotinib in Treating Patients with Esophageal or Gastroesophageal Cancer That Cannot be Removed by Surgery, http://www. clinicaltrials.gov/ct2/show/NCT0000539617;
66. A Phase II Study of 2 Doses of ZD6474 (Vandetanib) in combination with FOLFOX vs FOLFOX Alone for the Treatment of Colorectal Cancer, http://www.clinicaltrials.gov/ct2/show/NCT00500292.
67. Clinical Trials - Combination of Pemetrexed with Kinase Inhibitors: AStudy to Find the Best Dose of SU011248 When Given with Pemetrexed, Pemetrexed and Cisplatin or Pemetrexed and Carboplatin in Patients with Advanced Solid Tumors, http://www.clinicaltrials.gov/ct2/show/NCT00528619?term= pemetrexed&rank=1;
68. Efficacy Study Comparing ZD6474 in Combination with Pemetrexed and Pemetrexed Alone in 2nd Line NSCLC Patients (ZEAL), http://clinicaltrials.gov/ ct2/show/NCT00418886?term= pemetrexed&rank=2;
69. Docetaxel or Pemetrexed with or Without Cetuximab in Patients with Recurrent or Progressive Nonsmall Cell Lung Cancer, http://www.clinicaltrials. gov/ct2/show/NCT00095199?term=pemetrexed&rank=3;
70. A Phase II Trial of Lapatinib (TYKERB) A Pemetrexed (ALIMTA) Versus Pemetrexed in Advanced Non-small Cell Lung Cancer, http://www.clinicaltrials. gov/ct2/show/NCT00528281?term=pemetrexed&rank=7;
71. Study of Pemetrexed Versus Pemetrexed A Erlotinib as Treatment of Non-smallCellLungCancer, http://www.clinicaltrials.gov/ct2/show/NCT00447057? term=pemetrexed&rank=14;
72. Cisplatin, Imatinib Mesylate, and Pemetrexed in Malignant Mesothelioma Patients, http://www.clinicaltrials.gov/ct2/show/NCT00402766?term= pemetrexed&rank=17;
73. ZD6474 (Vandetanib) A Alimta Combo Study, http://www.clinicaltrials.gov/ ct2/show/NCT00506051?term=pemetrexed&rank=22;
74. Pemetrexed Disodium with or Without Sorafenib as Second-line Therapy in Treating Patients with Stage IIIB or Stave IV Non-small Cell Lung Cancer, http://www.clinicaltrials.gov/ct2/show/NCT00454194?term=pemetrexed&rank=31;
75. AZD6244 Versus Pemetrexed (Alimta®) in Patients with Non-small Cell Lung Cancer, Who Have Failed One or Two Prior Chemotherapy Regimen, http://clinicaltrials.gov/ct2/show/NCT00372788?term=pemetrexec&rank=32;
76. Randomized Phase III Trial of Pemetrexed vs Erlotinib in Pretreated Patients with NSCLC, http://clinicaltrials.gov/ct2/show/NCT00440414? term=pemetrexed&rank=34;
77. Vatalanib and Pemetrexed Disodium in Treating Patients with Advanced Solid Tumors, http://clinicaltrials.gov/ct2/show/NCT00390000?term= pemetrexed&rank=37;
78. Sorafenib Combined with Cisplatin and Etoposide or Carboplatin and Pemetrexed in Treating patients with Metastatic Solid Tumors, http://clinicaltrials.gov/ct2/show/NCT00573690? term=pemetrexed&rank=92;
79. Study in Patients with Advanced Non-small Cell Lung Cancer Treated with Pemetrexed and Carboplatin Plus or Minus Sorafenib (PECASO), http://clinicaltrials.gov/ct2/show/NCT00473486?term=pemetrexed&rank=98;
80. Chemotherapy for patients with Non-small Cell Lung CancerWhoAre Non-smokers, http://clinicaltrials.gov/ct2/show/NCT00409006? term=pemetrexed&rank=152;
81. Phase I/II Trial of Bevacizumab, Pemetrexed and Erlotinib in Elderly Patients with Non-small Cell Lung Cancer, http://clinicaltrials.gov/ct2/show/ NCT00351039?term=pemetrexed&rank=202;
82. AStudy to Evaluate Bevacizumab and Chemotherapy or Tarceva in Treating Recurrent or Refractory NSCLC (Non-small Cell Lung Cancer), http:// clinicaltrials.gov/ct2/show/NCT00095225?term=pemetrexed&rank=203;
83. A Study of Tarceva (Erlotinib) and Standard of Care Chemotherapy in Patients with Advanced, Recurrent or Metastatic Non-small Cell Lung Cancer (NSCLC), http://clinicaltrials.gov/ct2/show/NCT00556322?term= pemetrexed&rank=206.
84. Huber, P. E.; Bischof, M.; Jenne, J.; Heiland, S.; Peschke, P.; Saffrich, R.; Groene, H.-J.; Debus, J.; Lipson, K. E.; Abdollahi, A. Trimodal cancer treatment: Beneficial effects of combined antiangiogenesis, radiation, and chemotherapy. Cancer Res. 2005, 65, 3643-3655. (Pubitemid 40616341)
85. Schnell, J. R.; Dyson, H. J.; Wright, P. E. Structure, dynamics, and catalytic function of dihydrofolate reductase. Annu. Rev. Biophys. Biomol. Struct. 2004, 33, 119-140.
86. Carreras, C. W.; Santi, D. V. The catalytic mechanism and structure of thymidylate synthase. Annu. Rev. Biochem. 1995, 64, 721-762.
87. Lehman, N. L. Future potential of thymidylate synthase inhibitors in cancer therapy. Expert Opin. Invest. Drugs 2002, 11, 1775-1787.
88. Pizzorno, G. D. R. B. Cheng, Y.-C. Pyrimidine and Purine Antimetabolites. In Cancer Medicine; Holland, J. F., Frei, E., III, Eds.; B. C. Decker, Inc.: Hamilton, London. 2003, pp 739-744.
89. Rollins, K. D.; Lindley, C. Pemetrexed:Amultitargeted antifolate. Clin. Ther. 2005, 27, 1343-1382.
90. Clamp, A. R.; Schoeffski, P.; Valle, J. W.; Wilson, R. H.; Marreaud, S.; Govaerts, A. S.; Debois, M.; Lacombe, D.; Twelves, C.; Chick, J.; Jayson, G. C. A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer. Cancer Chemother. Pharmacol. 2008, 61, 579-585.
91. Showalter, H. D. H.; Bridges, A. J.; Zhou, H.; Sercel, A. D.; McMichael, A.; Fry, D. W. Tyrosine kinase inhibitors. 16. 6,5,6-Tricyclic benzothieno[3,2-d]pyrimidines and pyrimido[5,4-b]- and -[4,5-b]indoles as potent inhibitors of the epidermal growth factor receptor tyrosine kinase. J. Med. Chem. 1999, 42, 5464-5474.
92. Traxler, P. M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer, T.; Lydon, N. 4-(Phenylamino)pyrrolopyrimidines: Potent and selective, ATP site directed inhibitors of the EGF-receptor protein tyrosine kinase. J. Med. Chem. 1996, 39, 2285-2292.
93. Traxler, P.; Furet, P. Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol. Ther. 1999, 82, 195-206.
94. Gangjee, A.; Yang, J.; Ihnat, M. A.; Kamat, S. Antiangiogenic and antitumor agents. Design, synthesis, and evaluation of novel 2-amino-4-(3-bromoanilino)-6-benzylsubstituted pyrrolo[2,3-d]pyrimidines as inhibitors of receptor tyrosine kinases.Bioorg.Med.Chem. 2003, 11, 5155-5170.
95. Laufer, S.A.;Domeyer, D.M.; Scior,T.R.F.;Albrecht,W.;Hauser, D. R. J. Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. J. Med. Chem. 2005, 48, 710-722.
96. Abu Thaher, B.; Koch, P.; Schattel, V.; Laufer, S. Role of the hydrogen bonding heteroatom-Lys53 interaction between the p38α mitogen-activated protein (MAP) kinase and pyridinyl-substituted 5-membered heterocyclic ring inhibitors. J. Med. Chem. 2009, 52, 2613-2617.
97. Gangjee, A.; Lin, X.; Kisliuk, R. L.; McGuire, J. J. Synthesis of N-{4-[(2,4-Diamino-5-methyl-4,7-dihydro-3H- pyrrolo[2,3-d]pyrimidin-6-yl)thio] benzoyl}-L-glutamic Acid and N-{4-[(2-Amino-4-oxo-5-mthyl-4,7-dihydro-3H- pyrrolo[2,3-d]pyrimidin- 6-yl)thio]benzoyl}-L-glutamic Acid as Dual Inhibitors of Dihydrofolate Reductase and Thymidylate Synthase and as Potential Antitumor Agents. J. Med. Chem. 2005, 48, 7215-7222.
98. Rosowsky, A.; Forsch, R. A.; Freisheim, J. H.; Danenberg, P. V.; Moran, R. G.; Wick, M. M. Methotrexate analogs. 29. Effect of γ-aminobutyric acid spacers between the pteroyl and glutamate moieties on enzyme binding and cell growth inhibition. J. Med. Chem. 1986, 29, 1872-1876.
99. Gangjee, A.; Jain, H. D.; Kurup, S. Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I. Anti-Cancer Agents Med. Chem. 2007, 7, 524-542.
100. Gangjee,A.; Qiu, Y.; Li,W.; Kisliuk, R. L. Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: Classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno-[2,3-d]pyrimidine antifolates. J. Med. Chem. 2008, 51, 5789-5797.
101. Gangjee, A.; Li, W.; Yang, J.; Kisliuk, R. L. Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted- 6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors. J. Med. Chem. 2008, 51, 68-76.
102. Cody, V.; Luft Joseph, R.; Pangborn, W.; Gangjee, A. Analysis of three crystal structure determinations of a 5-methyl-6-N-methylanilino pyridopyrimidine antifolate complex with human dihydrofolate reductase. Acta Crystallogr. 2003, D59, 1603-1609. (Pubitemid 37105936)
103. Tripos Inc., 1699 South Hanley Road, St. Louis, MO 63144.
104. Davies, J. F., II; Delcamp, T. J.; Prendergast, N. J.; Ashford, V. A.; Freisheim, J. H.; Kraut, J. Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate. Biochemistry 1990, 29, 9467-9479. (Pubitemid 20329084)
105. Oefner, C.; D'Arcy, A.; Winkler, F. K. Crystal structure of human dihydrofolate reductase complexed with folate. Eur. J. Biochem. 1988, 174, 377-385.
106. Sayre, P. H.; Finer-Moore, J. S.; Fritz, T. A.; Biermann, D.; Gates, S. B.; MacKellar, W. C.; Patel, V. F.; Stroud, R. M. Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases. J. Mol. Biol. 2001, 313, 813-829.
107. Miyazaki, Y.; Matsunaga, S.; Tang, J.; Maeda, Y.; Nakano, M.; Philippe, R. J.; Shibahara, M.; Liu, W.; Sato, H.; Wang, L.; Nolte, R. T. Novel 4-aminofuro[2,3-d]pyrimidines as Tie-2 and VEGFR2 dual inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 2203-2207.
108. Mol, C. D.; Lim, K. B.; Sridhar, V.; Zou, H.; Chien, E. Y. T.; Sang, B.-C.; Nowakowski, J.; Kassel, D. B.; Cronin, C. N.; McRee,D. E. Structure of a c-Kit product complex reveals the basis for kinase transactivation. J. Biol. Chem. 2003, 278, 31461-31464.
109. MolecularOperating environment (MOE2007.09),C.C.G., Inc., 1255 University Street, Suite 1600, Montreal, Quebec, Canada, H3B 3X3.
110. Altschul, S. F.; Koonin, E. V. Iterated profile searches with PSIBLAST - a tool for discovery in protein databases. Trends Biochem. Sci. 1998, 23, 444-447.
111. Gallivan, J. P.; Dougherty, D. A. Cation-pi interactions in structural biology. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 9459-9464.
112. Mahboobi, S.; Uecker, A.; Sellmer, A.; Cenac, C.; Hoecher, H.; Pongratz, H.; Eichhorn, E.; Hufsky, H.; Truempler, A.; Sicker, M.; Heidel, F.; Fischer, T.; Stocking, C.; Elz, S.; Boehmer, F.-D.; Dove, S. Novel bis(1h-indol-2-yl) methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase. J. Med. Chem. 2006, 49, 3101-3115.
113. Henderson, E. A.; Bavetsias, V.; Theti, D. S.; Wilson, S. C.; Clauss, R.; Jackman, A. L. Targeting the a-folate receptor with cyclopenta[g]quinazoline- based inhibitors of thymidylate synthase. Bioorg. Med. Chem. 2006, 14, 5020-5042.
114. Griffith, J.; Black, J.; Faerman, C.; Swenson, L.; Wynn, M.; Lu, F.; Lippke, J.; Saxena, K. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol. Cell 2004, 13, 169-178. (Pubitemid 38183264)
115. Hennessy, B. T.; Smith, D. L.; Ram, P. T.; Lu, Y.; Mills, G. B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discovery 2005, 4, 988-1004.
116. Ihnat, M. A.; Kaltreider, R. C.; Thorpe, J. E.; Green, D. E.; Kamat, C. D.; Leeper, M.; Shanner, A. C.; Warnke, L. A.; Piconi, L.; Ceriello, A. Attenuated superoxide dismutase induction in retinal cells in response to intermittent high versus continuous high glucose. Am. J. Biochem. Biotechnol. 2007, 3, 16-23.
117. Schroeder, M. C.; Hamby, J. M.; Connolly, C. J.; Grohar, P. J.; Winters, R. T.; Barvian, M. R.; Moore, C. W.; Boushelle, S. L.; Crean, S. M.; Kraker, A. J.; Driscoll, D. L.; Vincent, P. W.; Elliott, W. L.; Lu, G. H.; Batley, B. L.; Dahring, T. K.; Major, T. C.; Panek, R. L.; Doherty, A. M.; Showalter, H. D. Soluble 2-substituted aminopyrido[2,3-d]pyrimidin-7-yl ureas. Structure-activity relationships against selected tyrosine kinases and exploration of in vitro and in vivo anticancer activity. J. Med. Chem. 2001, 44, 1915-1926.
118. Zaman, G. J. R.; Vink, P. M. F.; van den Doelen, A. A.; Veeneman, G. H.; Theunissen, H. J. M. Tyrosine kinase activity of purified recombinant cytoplasmic domain of platelet-derived growth factor β-receptor (β-PDGFR) and discovery of a novel inhibitor of receptor tyrosine kinases. Biochem. Pharmacol. 1999, 57, 57-64.
119. Mori, Y.; Hirokawa, T.; Aoki, K.; Satomi, H.; Takeda, S.; Aburada, M.; Miyamoto, K.-i. Structure activity relationships of quinoxalin-2-one derivatives as platelet-derived growth factor-β receptor (PDGF β R) inhibitors, derived from molecular modeling. Chem. Pharm. Bull. 2008, 56, 682-687.
120. Ward, J. J.; McGuffin, L. J.; Bryson, K.; Buxton, B. F.; Jones, D. T. The DISOPRED server for the prediction of protein disorder. Bioinformatics 2004, 20, 2138-2139. (Pubitemid 39236567)
121. Wilson, S. M.; Barsoum, M. J.; Wilson, B. W.; Pappone, P. A. Purine nucleotides modulate proliferation of brown fat preadipocytes. Cell Proliferation 1999, 32, 131-140.
122. Maurer, B. J.; Ihnat, M. A.; Morgan, C.; Pullman, J.; O'Brien, C.; Johnson, S. W.; Rasey, J. S.; Cornwell, M. M. Growth of human tumor cells in macroporous microcarriers results in p53-independent, decreased cisplatin sensitivity relative to monolayers. Mol. Pharmacol. 1999, 55, 938-947.
123. Fong, T. A.; Shawver, L. K.; Sun, L.; Tang, C.; App, H.; Powell, T. J.; Kim, Y. H.; Schreck, R.; Wang, X.; Risau, W.; Ullrich, A.; Hirth, K. P.; McMahon, G. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 1999, 59, 99-106. (Pubitemid 29062964)
124. Stockwell, B. R.; Haggarty, S. J.; Schreiber, S. L. High-throughput screening of small molecules in miniaturized mammalian cell-based assays involving post-translational modifications. Chem. Biol. 1999, 6, 71-83.
125. Gangjee, A.; Namjoshi, O. A.; Yu, J.; Ihnat, M. A.; Thorpe, J. E.; Warnke, L. A. Design, synthesis and biological evaluation of substituted pyrrolo[2,3-d]pyrimidines as multiple receptor tyrosine kinase inhibitors and antiangiogenic agents. Bioorg. Med. Chem. 2008, 16, 5514-5528.
126. Rosenzweig, K. E.; Youmell, M. B.; Palayoor, S. T.; Price, B. D. Radiosensitization of human tumor cells by the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. Clin. Cancer Res. 1997, 3, 1149-1156.
127. Kisliuk, R. L.; Strumpf, D.; Gaumont, Y.; Leary, R. P.; Plante, L. Diastereoisomers of 5,10-methylene-5,6,7,8-tetrahydropteroyl-Dglutamic acid. J. Med. Chem. 1977, 20, 1531-1533.
128. Wahba, A. J.; Friedkin, M. Enzymic synthesis of thymidylate. I. Early steps in the purification of thymidylate synthetase of Escherichia coli. J. Biol. Chem. 1962, 237, 3794-3801.
129. Davisson, V. J.; Sirawaraporn, W.; Santi, D. V. Expression of human thymidylate synthase in Escherichia coli. J. Biol. Chem. 1989, 264, 9145-9148.
130. Tsuda, H.; Sakaguchi, M.; Kawakita, M.; Nakazawa, S.; Mori, T.; Takatsuki, K. Alteration of cell cycle progression in human leukemia cell line (KOPM-28) induced by 12-o-tetradecanoylphorbol13-acetate. Int. J. Cell Cloning 1988, 6, 209-220. (Pubitemid 18139697)
131. Iliakis, G.; Nusse, M. Arrest of irradiated G1, S, or G2 cells at mitosis using nocodazole promotes repair of potentially lethal damage. Radiat. Res. 1984, 99, 346-351.
132. Lucarelli, E.; Sangiorgi, L.; Benassi, S.; Donati, D.; Gobbi, G. A.; Picci, P.; Vacca, A.; Ribatti, D. Angiogenesis in lipoma: An experimental study in the chick embryo chorioallantoic membrane. Int. J. Mol. Med. 1999, 4, 593-596.
133. Romanoff, A. L. Biochemistry of the Avian Embryo: A Quantitative Analysis of Prenatal Development; Interscience: New York, 1967; 398 pp.
134. Hanna, N.; Fidler, I. J. Role of natural killer cells in the destruction of circulating tumor emboli. J. Natl. Cancer Inst. 1980, 65, 801-809.
135. Hanna, N.; Davis, T. W.; Fidler, I. J. Environmental and genetic factors determine the level of NK activity of nude mice and affect their suitability as models for experimental metastasis. Int. J. Cancer 1982, 30, 371-376.