Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier for cellular entry

Journal of Medicinal Chemistry

Volumn 53, Issue 3, 2010, Pages 1306-1318

  Wang, Lei ^a   Cherian, Christina ^b   Desmoulin, Sita Kugel ^c   Polin, Lisa ^b,c   Deng, Yijun ^c   Wu, Jianmei ^b   Hou, Zhanjun ^b   White, Kathryn ^b,c   Kushner, Juiwanna ^b,c   Matherly, Larry H ^b,c   Gangjee, Aleem ^a  

^a DUQUESNE UNIVERSITY   (United States)

^b KARMANOS CANCER INSTITUTE   (United States)

^c WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 ([5 [4 (2 AMINO 4 OXO 4,7 DIHYDRO 3H PYRROLO[2,3 D]PYRIMIDIN 6 YL)BUTYL]THIOPHENE 2 CARBONYL]AMINO)PENTANEDIOIC ACID; 2 ([5 [5 (2 AMINO 4 OXO 4,7 DIHYDRO 3H PYRROLO[2,3 D]PYRIMIDIN 6 YL)PENTYL]THIOPHENE 2 CARBONYL]AMINO)PENTANEDIOIC ACID; 2 ([5 [6 (2 AMINO 4 OXO 4,7 DIHYDRO 3H PYRROLO[2,3 D]PYRIMIDIN 6 YL)HEXYL]THIOPHENE 2 CARBONYL]AMINO)PENTANEDIOIC ACID; ANTINEOPLASTIC AGENT; CARBOXYLIC ACID; FOLATE RECEPTOR; FOLIC ACID ANTAGONIST; PHOSPHORIBOSYLGLYCINAMIDE FORMYLTRANSFERASE; PYRROLO[2,3 D]PYRIMIDINE DERIVATIVE; REDUCED FOLATE CARRIER; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANTINEOPLASTIC ACTIVITY; ARTICLE; BIOSYNTHESIS; CANCER STAGING; CONTROLLED STUDY; DRUG DOSE REGIMEN; DRUG EFFICACY; DRUG STRUCTURE; DRUG SYNTHESIS; FEMALE; HUMAN; HUMAN CELL; HYDROGENATION; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; POLYMERIZATION; SAPONIFICATION; SCID MOUSE; SONOGASHIRA REACTION; TREATMENT DURATION; TUMOR CELL;

ANIMALS; ANTINEOPLASTIC AGENTS; CARCINOMA, SQUAMOUS CELL; CARRIER PROTEINS; CELL PROLIFERATION; CELLS, CULTURED; CHO CELLS; CRICETINAE; CRICETULUS; FEMALE; FOLIC ACID ANTAGONISTS; HUMANS; MEMBRANE TRANSPORT PROTEINS; MICE; MICE, INBRED ICR; MICE, SCID; OVARIAN NEOPLASMS; PURINES; PYRIMIDINES; RECEPTORS, CELL SURFACE;

EID: 77249090272     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm9015729     Document Type: Article

References (46)

1. Monahan, B. P.; Allegra, C. J. Antifolates. In Cancer Chemotherapy and Biotherapy, 4th ed.; Chabner, B. A., Longo, D. L., Eds.; Lippincott-Raven: Philadelphia, 2001; pp 109-148.
2. Hazarika, M.; White, R. M.; Johnson, J. R.; Pazdur, R. FDA Drug Approval Summaries: Pemetrexed (Alimta). Oncologist 2004, 9, 482-488.
3. Scagliotti, G. V.; Parikh, P.; von Pawel, J.; Biesma, B.; Vansteenkiste, J.; Manegold, C.; Serwatowski, P.; Gatzemeier, U.; Digumarti, R.; Zukin, M.; Lee, J. S.; Mellemgaard, A.; Park, K.; Patil, S.; Rolski, J.; Goksel, T.; de Marinis, F.; Simms, L.; Sugarman, K. P.; Gandara, D. Phase III Study Comparing Cisplatin Plus Gemcitabine with Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients with Advanced-Stage Non-Small-Cell Lung Cancer. J. Clin. Oncol. 2008, 26, 3543-3551.
4. Ciuleanu, T.; Brodowicz, T.; Zielinski, C; Kim, J. H.; Krzakowski, M.; Laack, E.; Wu, Y. L.; Bover, I.; Begbie, S.; Tzekova, V.; Cucevic, B.; Pereira, J. R.; Yang, S. H.; Madhavan, J.; Sugarman, K. P.; Peterson, P.; John, W. J.; Krejcy, K.; Belani, C. P. Maintenance Pemetrexed Plus Best Supportive Care versus Placebo Plus Best Supportive Care for Non-Small-Cell Lung Cancer: A Randomised, Double-Blind, Phase 3 Study. Lancet 2009, 374, 1432-1440.
5. Chu, E.; Callender, M. A.; Farrell, M. P.; Schmitz, J. C. Thymidy-late Synthase Inhibitors as Anticancer Agents: From Bench to Bedside. Cancer Chemother. Pharmacol. 2003, 52 (Suppl. 1), S80-89.
6. Matherly, L. H.; Goldman, I. D. Membrane Transport of Folates. Vitam. Horm. 2003, 66, 403-456.
7. Matherly, L. H.; Hou, Z.; Deng, Y. Human Reduced Folate Carrier: Translation of Basic Biology to Cancer Etiology and Therapy. Cancer Metastasis Rev. 2007, 26, 111-128.
8. Zhao, R.; Matherly, L. H.; Goldman, I. D. Membrane Transporters and Folate Homeostasis; Intestinal Absorption, Transport into Systemic Compartments and Tissues. Expert Rev. Mol. Med. 2009, 11, No. e4.
9. Salazar, M. D.; Ratnam, M. The Folate Receptor: What Does It Promise in Tissue-Targeted Therapeutics? Cancer Metastasis Rev. 2007, 26, 141-152.
10. Elnakat, H.; Ratnam, M. Distribution, Functionality and Gene Regulation of Folate Receptor Isoforms: Implications in Targeted Therapy. Adv. Drug Delivery 2004, 56, 1067-1084.
11. Qiu, A.; Jansen, M.; Sakaris, A.; Min, S. H.; Chattopadhyay, S; Tsai, E.; Sandoval, C.; Zhao, R; Akabas, M. H.; Goldman, I. D. Identification of an Intestinal Folate Transporter and the Molecular Basis for Hereditary Folate Malabsorption. Cell 2006, 127, 917-928.
12. Zhao, R.; Goldman, I. D. The Molecular Identity and Characterization of a Proton-Coupled Folate Transporter-PCFT; Biological Ramifications and Impact on the Activity of Pemetrexed. Cancer Metastasis Rev. 2007, 26, 129-139.
13. Reddy, J. A.; Haneline, L. S.; Srour, E. F.; Antony, A. C.; Clapp, D. W.; Low, P. S. Expression and Functional Characterization of the Beta-Isoform of the Folate Receptor on CD34(+) Cells. Blood 1999, 93, 3940-3948.
14. Leamon, C. P.; Reddy, J. A.; Vlahov, I. R.; Westrick, E.; Dawson, A.; Dorton, R.; Vetzel, M.; Santhapuram, H. K.; Wang, Y. Preclinical Antitumor Activity of a Novel Folate-Targeted Dual Drug Conjugate. Mol. Pharmaceutics 2007, 4, 659-667.
15. Lu, Y.; Wu, J.; Gonit, M.; Yang, X.; Lee, A.; Xiang, G.; Li, H.; Liu, S.; Marcucci, G.; Ratnam, M.; Lee, R. J. Role of Formulation Composition in Folate Receptor-Targeted Liposomal Doxorubicin Delivery to Acute Myelogenous Leukemia Cells. Mol. Pharmaceutics 2007, 4, 707-712.
16. Muller, C.; Forrer, F.; Schibli, R.; Krenning, E. P.; de Jong, M. SPECT Study of Folate Receptor-Positive Malignant and Normal Tissues in Mice Using a Novel 99mTc-Radiofolate. J. Nucl. Med. 2008, 49, 310-317.
17. Deng, Y.; Wang, Y.; Cherian, C.; Hou, Z.; Buck, S. A.; Matherly, L. H.; Gangjee, A. Synthesis and Discovery of High Affinity Folate Receptor-Specific Glycinamide Ribonucleotide Formyltransferase Inhibitors with Antitumor Activity. J. Med. Chem. 2008, 51, 5052-5063.
18. Deng, Y.; Zhou, X.; Kugel Desmoulin, S.; Wu, J.; Cherian, C.; Hou, Z.; Matherly, L. H.; Gangjee, A. Synthesis and Biological Activity of a Novel Series of 6-Substituted Thieno [2,3-d] pyrimidine Antifolate Inhibitors of Purine Biosynthesis with Selectivity for High Affinity Folate Receptors over the Reduced Folate Carrier and Proton-Coupled Folate Transporter for Cellular Entry. J. Med. Chem. 2009, 52, 2940-2951.
19. Jansen, G. Receptor- and Carrier-Mediated Transport Systems for Folates and Antifolates: Exploitation for Folate Chemotherapy and Immunotherapy. In Anticancer Development Guide: Antifolate Drugs in Cancer Therapy; Jackman, A. L., Ed.; Humana Press Inc.: Totowa, NJ, 1999; pp 293-321.
20. Jones, T. R.; Calvert, A. H.; Jackman, A. L.; Eakin, M. A.; Smithers, M. J.; Betteridge, R. F.; Newell, D. R.; Hayter, A. J.; Stocker, A.; Harland, S. J.; et al. Quinazoline Antifolates Inhibiting Thymidylate Synthase: Variation of the N10 Substituent. J. Med. Chem. 1985, 28, 1468-1476.
21. Jones, T. R.; Calvert, A. H.; Jackman, A. L.; Brown, S. J.; Jones, M.; Harrap, K. R. A Potent Antitumour Quinazoline Inhibitor of Thymidylate Synthetase: Synthesis, Biological Properties and Therapeutic Results in Mice. Eur. J. Cancer 1981, 17, 11-19.
22. Theti, D. S.; Bavetsias, V.; Skelton, L. A.; Titley, J.; Gibbs, D.; Jansen, G.; Jackman, A. L. Selective Delivery of CB300638, A Cyclopenta[g]quinazoline-based Thymidylate Synthase Inhibitor into Human Tumor Cell Lines Overexpressing the Alpha-Isoform of the Folate Receptor. Cancer Res. 2003, 63, 3612-3618.
23. Gibbs, D. D.; Theti, D. S.; Wood, N.; Green, M.; Raynaud, F.; Valenti, M.; Forster, M. D.; Mitchell, F.; Bavetsias, V.; Henderson, E.; Jackman, A. L. BGC 945, A Novel Tumor-Selective Thymidylate Synthase Inhibitor Targeted to Alpha-Folate Receptor-Overexpressing Tumors. Cancer Res. 2005, 65, 11721-11728.
24. Kugel Desmoulin, S.; Wang, Y.; Wu, J.; Hou, Z.; Cherian, C.; Gangjee, A.; Matherly, L. H. Discovery of a Glycinamide Ribonucleotide Formyltransferase Inhibitor with Solid Tumor Selectivity via Its Transport by the Proton-Coupled Folate Transporter. Abstr., Am. Assoc. Cancer Res. 2009, 50, 404.
25. Wang, L.; Kugel Desmoulin, S.; Deng, Y.; Polin, L.; Cherian, C.; Matherly, L. H.; Gangjee, A. The Design, Synthesis and in Vitro and in Vivo Evaluation of Selective FR α and β and PCFT Substrates with Potent GARFTase Inhibitory Activity as Antitumor Agents. Abstr., Am. Assoc. Cancer Res. 2009, 50, 463.
26. Ray, M. S.; Muggia, F. M.; Leichman, G.; Grunberg, S. M.; Nelson, R. L.; Dyke, R. W.; Moran, R. G. Phase I Study of (6R)-5,10-Dideazatetrahydrofolate: A Folate Antimetabolite Inhibitory to De Novo Purine Synthesis. J. Natl. Cancer Inst. 1993, 85, 1154-1159.
27. Cole, J. T.; Gralla, R. J.; Kardinal, C. G.; Rivera, N. P. Lometrexol (DDATHF): Phase I Trial of a Weekly Schedule of This New Antifolate. Proc. Am. Assoc. Cancer Res. 1992, 33, 2468.
28. Wedge, S. R.; Laohavinij, S.; Taylor, G. A.; Newell, D. R.; Charlton, C. J.; Proctor, M.; Chapman, R.; Simmons, D.; Oakey, A.; Gumbrell, L.; Calvert, A. H. Proc. Am. Assoc. Cancer Res. 1993, 34, 1629.
29. Budman, D. R.; Johnson, R.; Barile, B.; Bowsher, R. R.; Vinciguerra, V.; Allen, S. L.; Kolitz, J.; Ernest, C. S., II; Kreis, W.; Zervos, P.; Walling, J. Phase I and Pharmacokinetic Study of LY309887: A Specific Inhibitor of Purine Biosynthesis. Cancer Chemother. Pharmacol. 2001, 47, 525-531.
30. Boritzki, T. J.; Zhang, C.; Bartlett, C. A.; Jackson, R. C. AG2034 A GARFT Inhibitor With Selective Cytotoxicity to Cells that Lack a G1 Checkpoint. In Anticancer Drug Development Guide: Antifolate Drugs in Cancer Therapy; Jackman, A. L., Ed.; Humana Press Inc.: Totowa, NJ, 1999; pp 281-292.
31. McLeod, H. L.; Cassidy, J.; Powrie, R. H.; Priest, D. G.; Zorbas, M. A.; Synold, T. W.; Shibata, S.; Spicer, D.; Bissett, D.; Pithavala, Y. K.; Collier, M. A.; Paradiso, L. J.; Roberts, J. D. Pharmacokinetic and Pharmacodynamic Evaluation of the Clycinamide Ribonucleotide Formyltransferase Inhibitor AG2034. Clin. Cancer. Res. 2000, 6, 2677-2684.
32. Wong, S. C.; Proefke, S. A.; Bhushan, A.; Matherly, L. H. Isolation of Human cDNAs that Restore Methotrexate Sensitivity and Reduced Folate Carrier Activity in Methotrexate Transport-Defective Chinese Hamster Ovary Cells. J. Biol. Chem. 1995, 270, 17468-17475.
33. Flintoff, W. F.; Davidson, S. V.; Siminovitch, L. Isolation and Partial Characterization of Three Methotrexate-Resistant Phenotypes from Chinese Hamster Ovary Cells. Som. Cell Genet. 1976, 2, 245-261.
34. Beardsley, G. P.; Moroson, B. A.; Taylor, E. C.; Moran, R. G. A New Folate Antimetabolite, 5, 10-Dideaza-5, 6, 7, 8-tetrahydrofolate is a Potent Inhibitor of de novo purine Synthesis. J. Biol. Chem. 1989, 264, 328-333.
35. Shih, C.; Thornton, D. E. Preclinical Pharmacology Studies on the Clinical Development of a Novel Multitargeted Antifolate, MTA (LY231514). In Anticancer Development Guide: Antifolate Drugs in Cancer Therapy; Jackman, A. L., Ed.; Humana Press Inc.: Totowa, NJ, 1999; pp 183-201.
36. Sanghani, S. P.; Moran, R. G. Tight Binding of Folate Substrates and Inhibitors to Recombinant Mouse Glycinamide Ribonucleotide Formyltransferase. Biochemistry 1997, 36, 10506-10516.
37. Zhao, R.; Goldman, I. D. Resistance to Antifolates. Oncogene 2003, 22, 7431-7457.
38. Varela-Moreiras, G.; Selhub, J. Long Term Folate Deficiency Alters Folate Content and Distribution Differently in Rat Tissues. J. Nutr. 1992, 122, 986-991.
39. Ganji, V.; Kafai, M. R. Demographic, Lifestyle, and Health Characteristics and Serum B Vitamin Status Are Determinants of Plasma Total Homocysteine Concentration in the Post-Folic Acid Fortification Period, 1999-2004. J. Nutr. 2009, 139, 345-52.
40. Raghunand, N.; Altbach, M. I.; van Sluis, R.; Baggett, B.; Taylor, C. W.; Bhujwalla, Z. M.; Gillies, R. J. Plasmalemmal pH-Gradients in Drug-Sensitive and Drug-Resistant MCF-7 Human Breast Carcinoma Xenografts Measured by 31P Magnetic Resonance Spectroscopy. Biochem. Pharmacol. 1999, 57, 309-312.
41. Lowry, O. H.; Rosebrough, N. J.; Farr, A. L.; Randall, R. J. Protein Measurement with the Folin Phenol Reagent. J. Biol. Chem. 1951, 193, 265-275.
42. Corbett, T.; Valeriote, F.; LoRusso, P.; Polin, L.; Panchapor, C.; Pugh, S.; White, K.; Knight, J.; Demchik, L.; Jones, J.; Jones, L.; Lowichik, N.; Biernat, L.; Foster, B.; Wozniak, A.; Lisow, L.; Valdivieso, M.; Baker, L.; Leopold, W.; Sebolt, J.; Bissery, M.-C.; Mattes, K.; Dzubow, J.; Rake, J.; Perni, R.; Wentland, M.; Coughlin, S.; Shaw, J. M.; Liverside, G.; Liversidge, E.; Bruno, J.; Sarpotdar, P.; Moore, R.; Patterson, G. Tumor Models and the Discovery and Secondary Evaluation of Solid Tumor Active Agents. Int. J. Pharmacogn. 1995, 33 (Suppl.), 102-122.
43. Corbett, T. H.; Valeriote, F. A.; Demchik, L.; Lowichik, N.; Polin, L.; Panchapor, C.; Pugh, S.; White, K.; Kushner, J.; Rake, J.; Wentland, M.; Golakoti, T.; Hetzel, C.; Ogino, J.; Patterson, G.; Moore, R. Discovery of Cryptophycin-1 and BCN-183577: Examples of Strategies and Problems in the Detection of Antitumor Activity in Mice. Invest. New Drugs 1997, 15, 207-218.
44. Corbett, T. H.; Polin, L.; Roberts, B. J.; Lawson, A. J.; Leopold, W. R., III; White, K.; Kushner, J.; Paluch, J.; Hazeldine, S.; Moore, R.; Rake, J.; Horwitz, J. P. Transplantable Syngeneic Rodent Tumors: Solid Tumors of Mice. In Tumor Models in Cancer Research; Teicher, B., Ed.; Humana Press Inc.: Totowa, NJ, 2002l Chapter 3, pp 41-71.
45. Corbett, T.; Polin, L.; LoRusso, P.; Valeriote, F.; Panchapor, C.; Pugh, S.; White, K. P.; Knight, J.; Demchik, L.; Jones, J.; Jones, L.; Lisow, L. In Vivo Methods for Screening and Preclinical Testing; Use of Rodent Solid Tumors for Drug Discovery. In Anticancer Drug Development Guide, 2nd ed.; Teicher, B. A., Andrews, P. A., Eds.; Humana Press Inc.: Totowa, NJ, 2004; Chapter 6, pp 99-124.
46. Polin, L.; Valeriote, F.; White, K.; Panchapor, C.; Pugh, S.; Knight, J.; LoRusso, P.; Hussain, M; Liversidge, E.; Shaw, M.; Golakoti, T.; Patterson, G.; Moore, R.; Corbett, T. H. Treatment of Human Prostate Tumors PC-3 and TSU-PR1 with Standard and Investigational Agents in SCID Mice. Invest. New Drugs 1997, 15, 99-108.