Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

Golani, Lalit K.; Wallace-Povirk, Adrianne; Deis, Siobhan M.; Wong, Jennifer; Ke, Jiyuan; Gu, Xin; Raghavan, Sudhir; Wilson, Mike R.; Li, Xinxin; Polin, Lisa; de Waal, Parker W.; White, Kathryn; Kushner, Juiwanna; O’Connor, Carrie; Hou, Zhanjun; Xu, H. Eric; Melcher, Karsten; Dann, III, Charles E.; Matherly, Larry H.; Gangjee, Aleem

doi:10.1021/acs.jmedchem.6b00594

Title: Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

Journal Article · Tue Jul 26 00:00:00 EDT 2016 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.6b00594· OSTI ID:1330265

Golani, Lalit K. ^[1]; Wallace-Povirk, Adrianne ^[2]; Deis, Siobhan M. ^[3]; Wong, Jennifer ^[3]; Ke, Jiyuan ^[4]; Gu, Xin ^[4]; Raghavan, Sudhir ^[1]; Wilson, Mike R. ^[5]; Li, Xinxin ^[1]; Polin, Lisa ^[6]; de Waal, Parker W. ^[4]; White, Kathryn ^[6]; Kushner, Juiwanna ^[6]; O’Connor, Carrie ^[2]; Hou, Zhanjun ^[6]; Xu, H. Eric ^[7]; Melcher, Karsten ^[4]; Dann, III, Charles E. ^[3]; Matherly, Larry H. ^[6]; Gangjee, Aleem ^[1]

Duquesne Univ., Pittsburgh, PA (United States)
Barbara Ann Karmanos Cancer Inst., Detroit, MI (United States)
Indiana Univ., Bloomington, IN (United States)
Van Andel Research Inst., Grand Rapids, MI (United States)
Wayne State Univ. School of Medicine, Detroit, MI (United States)
Barbara Ann Karmanos Cancer Inst., Detroit, MI (United States); Wayne State Univ. School of Medicine, Detroit, MI (United States)
Van Andel Research Inst., Grand Rapids, MI (United States); Chinese Academy of Sciences, Shanghai (China)

Targeted antifolates with heteroatom replacements of the carbon vicinal to the phenyl ring in 1 by N (4), O (8), or S (9), or with N-substituted formyl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (FR) α and β or the proton-coupled folate transporter. Results show increased in vitro antiproliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4–9 over the CH2 analogue 1. Compounds 4–9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRα and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRα and GARFTase. In mice bearing IGROV1 ovarian tumor xenografts, 4 was highly efficacious. Here, our results establish that heteroatom substitutions in the 3-atom bridge region of 6-substituted pyrrolo[2,3-d]pyrimidines related to 1 provide targeted antifolates that warrant further evaluation as anticancer agents.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC); Michigan Economic Development Corporation; Michigan Technology Tri-Corridor; National Inst. of Health; National Science Foundation (NSF); Ministry of Science and Technology

Grant/Contract Number:: AC02-06CH11357; 085P1000817; P30 CA022453; CA53535; CA125153; CA152316; CA166711; GM094472; DK071662; GM102545; GM104212; NSF91217311; 2012ZX09301001; 2012CB910403; 2013CB910600; XDB08020303; 2013ZX09507001

OSTI ID:: 1330265

Journal Information:: Journal of Medicinal Chemistry, Vol. 59, Issue 17; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 27 works

Citation information provided by
Web of Science

References (68)

Human reduced folate carrier: translation of basic biology to cancer etiology and therapy Matherly, Larry H.; Hou, Zhanjun; Deng, Yijun Cancer and Metastasis Reviews, Vol. 26, Issue 1 https://doi.org/10.1007/s10555-007-9046-2	journal	March 2007
Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy Elnakat, H. Advanced Drug Delivery Reviews, Vol. 56, Issue 8 https://doi.org/10.1016/j.addr.2004.01.001	journal	April 2004
The molecular identity and characterization of a Proton-Coupled Folate Transporter—PCFT; biological ramifications and impact on the activity of pemetrexed—12 06 06 Zhao, Rongbao; Goldman, I. David Cancer and Metastasis Reviews, Vol. 26, Issue 1 https://doi.org/10.1007/s10555-007-9047-1	journal	March 2007
The human proton-coupled folate transporter Desmoulin, Sita Kugel; Hou, Zhanjun; Gangjee, Aleem Cancer Biology & Therapy, Vol. 13, Issue 14 https://doi.org/10.4161/cbt.22020	journal	December 2012
Identification of an Intestinal Folate Transporter and the Molecular Basis for Hereditary Folate Malabsorption Qiu, Andong; Jansen, Michaela; Sakaris, Antoinette Cell, Vol. 127, Issue 5 https://doi.org/10.1016/j.cell.2006.09.041	journal	December 2006
Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction Qiu, Andong; Min, Sang Hee; Jansen, Michaela American Journal of Physiology-Cell Physiology, Vol. 293, Issue 5 https://doi.org/10.1152/ajpcell.00202.2007	journal	November 2007
Functional characterization of PCFT/HCP1 as the molecular entity of the carrier-mediated intestinal folate transport system in the rat model Inoue, Katsuhisa; Nakai, Yasuhiro; Ueda, Sayaka American Journal of Physiology-Gastrointestinal and Liver Physiology, Vol. 294, Issue 3 https://doi.org/10.1152/ajpgi.00309.2007	journal	March 2008
Low-Dose Methotrexate Pharmacokinetics and Pharmacodynamics in the Therapy of Severe Psoriasis Chladek, Jaroslav; Grim, Jiri; Martinkova, Jirina Basic Clinical Pharmacology Toxicology, Vol. 96, Issue 3 https://doi.org/10.1111/j.1742-7843.2005.pto960318.x	journal	March 2005
Antifolates in cancer therapy: Structure, activity and mechanisms of drug resistance Gonen, Nitzan; Assaraf, Yehuda G. Drug Resistance Updates, Vol. 15, Issue 4 https://doi.org/10.1016/j.drup.2012.07.002	journal	August 2012
The Antifolates Visentin, Michele; Zhao, Rongbao; Goldman, I. David Hematology/Oncology Clinics of North America, Vol. 26, Issue 3 https://doi.org/10.1016/j.hoc.2012.02.002	journal	June 2012
Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis Wessels, J. A. M.; Huizinga, T. W. J.; Guchelaar, H. -J. Rheumatology, Vol. 47, Issue 3 https://doi.org/10.1093/rheumatology/kem279	journal	November 2007
Preclinical Pharmacology Studies and the Clinical Development of a Novel Multitargeted Antifolate, MTA (LY231514) Shih, Chuan; Thornton, Donald E. Antifolate Drugs in Cancer Therapy https://doi.org/10.1007/978-1-59259-725-3_8	book	January 1999
Therapeutic Targeting of a Novel 6-Substituted Pyrrolo [2,3-d]pyrimidine Thienoyl Antifolate to Human Solid Tumors Based on Selective Uptake by the Proton-Coupled Folate Transporter Kugel Desmoulin, Sita; Wang, Lei; Hales, Eric Molecular Pharmacology, Vol. 80, Issue 6 https://doi.org/10.1124/mol.111.073833	journal	September 2011
6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Targeted Antifolates for Folate Receptor α and the Proton-Coupled Folate Transporter in Human Tumors Wang, Lei; Wallace, Adrianne; Raghavan, Sudhir Journal of Medicinal Chemistry, Vol. 58, Issue 17 https://doi.org/10.1021/acs.jmedchem.5b00801	journal	August 2015
Targeting Nonsquamous Nonsmall Cell Lung Cancer via the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]Pyrimidine Thienoyl Antifolates Wilson, Mike R.; Hou, Zhanjun; Yang, Si Molecular Pharmacology, Vol. 89, Issue 4 https://doi.org/10.1124/mol.115.102798	journal	February 2016
The folate receptor: What does it promise in tissue-targeted therapeutics? Salazar, Marcela D’Alincourt; Ratnam, Manohar Cancer and Metastasis Reviews, Vol. 26, Issue 1 https://doi.org/10.1007/s10555-007-9048-0	journal	February 2007
Folate-Targeted Therapies for Cancer Xia, Wei; Low, Philip S. Journal of Medicinal Chemistry, Vol. 53, Issue 19 https://doi.org/10.1021/jm100509v	journal	July 2010
Folate Receptor β Is Expressed by Tumor-Associated Macrophages and Constitutes a Marker for M2 Anti-inflammatory/Regulatory Macrophages Puig-Kröger, Amaya; Sierra-Filardi, Elena; Domínguez-Soto, Angeles Cancer Research, Vol. 69, Issue 24 https://doi.org/10.1158/0008-5472.CAN-09-2050	journal	December 2009
Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis Condeelis, John; Pollard, Jeffrey W. Cell, Vol. 124, Issue 2 https://doi.org/10.1016/j.cell.2006.01.007	journal	January 2006
Vintafolide: a novel targeted therapy for the treatment of folate receptor expressing tumors Vergote, Ignace; Leamon, Christopher P. Therapeutic Advances in Medical Oncology, Vol. 7, Issue 4 https://doi.org/10.1177/1758834015584763	journal	May 2015
Role of the folate receptor in ovarian cancer treatment: evidence, mechanism, and clinical implications Vergote, Ignace B.; Marth, Christian; Coleman, Robert L. Cancer and Metastasis Reviews, Vol. 34, Issue 1 https://doi.org/10.1007/s10555-014-9539-8	journal	January 2015
PRECEDENT: A Randomized Phase II Trial Comparing Vintafolide (EC145) and Pegylated Liposomal Doxorubicin (PLD) in Combination Versus PLD Alone in Patients With Platinum-Resistant Ovarian Cancer Naumann, R. Wendel; Coleman, Robert L.; Burger, Robert A. Journal of Clinical Oncology, Vol. 31, Issue 35 https://doi.org/10.1200/JCO.2013.49.7685	journal	December 2013
BGC 945, a Novel Tumor-Selective Thymidylate Synthase Inhibitor Targeted to α-Folate Receptor–Overexpressing Tumors Gibbs, David D.; Theti, Davinder S.; Wood, Nadya Cancer Research, Vol. 65, Issue 24 https://doi.org/10.1158/0008-5472.CAN-05-2034	journal	December 2005
Synthesis and Discovery of High Affinity Folate Receptor-Specific Glycinamide Ribonucleotide Formyltransferase Inhibitors with Antitumor Activity Deng, Yijun; Wang, Yiqiang; Cherian, Christina Journal of Medicinal Chemistry, Vol. 51, Issue 16 https://doi.org/10.1021/jm8003366	journal	August 2008
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 Wang, Lei; Cherian, Christina; Kugel Desmoulin, Sita Journal of Medicinal Chemistry, Vol. 53, Issue 3 https://doi.org/10.1021/jm9015729	journal	January 2010
Synthesis, Biological, and Antitumor Activity of a Highly Potent 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Antifolate Inhibitor with Proton-Coupled Folate Transporter and Folate Receptor Selectivity over the Reduced Folate Carrier That Inhibits β-Glycinamide Ribonucleotide Formyltransferase Wang, Lei; Desmoulin, Sita Kugel; Cherian, Christina Journal of Medicinal Chemistry, Vol. 54, Issue 20 https://doi.org/10.1021/jm200739e	journal	September 2011
Synthesis and Biological Activity of 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Inhibitors of de Novo Purine Biosynthesis with Selectivity for Cellular Uptake by High Affinity Folate Receptors and the Proton-Coupled Folate Transporter over the Reduced Folate Carrier Wang, Lei; Cherian, Christina; Kugel Desmoulin, Sita Journal of Medicinal Chemistry, Vol. 55, Issue 4 https://doi.org/10.1021/jm201688n	journal	February 2012
Discovery of 5-Substituted Pyrrolo[2,3- d ]pyrimidine Antifolates as Dual-Acting Inhibitors of Glycinamide Ribonucleotide Formyltransferase and 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase in De Novo Purine Nucleotide Biosynthesis: Implications of Inhibiting 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase to AMPK Activation and Antitumor Activity Mitchell-Ryan, Shermaine; Wang, Yiqiang; Raghavan, Sudhir Journal of Medicinal Chemistry, Vol. 56, Issue 24 https://doi.org/10.1021/jm401328u	journal	December 2013
Tumor-Targeting with Novel Non-Benzoyl 6-Substituted Straight Chain Pyrrolo[2,3- d ]pyrimidine Antifolates via Cellular Uptake by Folate Receptor α and Inhibition of de Novo Purine Nucleotide Biosynthesis Wang, Yiqiang; Cherian, Christina; Orr, Steven Journal of Medicinal Chemistry, Vol. 56, Issue 21 https://doi.org/10.1021/jm401139z	journal	October 2013
Structure–Activity Profiles of Novel 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Antifolates with Modified Amino Acids for Cellular Uptake by Folate Receptors α and β and the Proton-Coupled Folate Transporter Golani, Lalit K.; George, Christina; Zhao, Sai Journal of Medicinal Chemistry, Vol. 57, Issue 19 https://doi.org/10.1021/jm501113m	journal	September 2014
Preclinical and Clinical Evaluation of the Glycinamide Ribonucleotide Formyltransferase Inhibitors Lometrexol and LY309887 Mendelsohn, Laurane G.; Worzalla, John F.; Walling, Jackie M. Antifolate Drugs in Cancer Therapy https://doi.org/10.1007/978-1-59259-725-3_12	book	January 1999
AG2034: a novel inhibitor of glycinamide ribonucleotide formyltransferase Boritzki, Theodore J.; Barlett, Charlotte A.; Zhang, Cathy Investigational New Drugs, Vol. 14, Issue 3 https://doi.org/10.1007/BF00194533	journal	September 1996
Phase I dose-escalation and pharmacokinetic study of a novel folate analogue AG2034 Bissett, D.; McLeod, H. L.; Sheedy, B. British Journal of Cancer, Vol. 84, Issue 3 https://doi.org/10.1054/bjoc.2000.1601	journal	February 2001
Phase I and pharmacokinetic study of LY309887: a specific inhibitor of purine biosynthesis Budman, Daniel; Johnson, Robert; Barile, Barbara Cancer Chemotherapy and Pharmacology, Vol. 47, Issue 6 https://doi.org/10.1007/s002800000272	journal	June 2001
Phase I Study of (6R)-5, 10-Dideazatetrahydrofolate: a Folate Antimetabolite Inhibitory to De Novo Purine Synthesis Ray, M. S.; Muggia, F. M.; Leichman, C. G. JNCI Journal of the National Cancer Institute, Vol. 85, Issue 14 https://doi.org/10.1093/jnci/85.14.1154	journal	July 1993
Rational Design, Synthesis, Evaluation, and Crystal Structure of a Potent Inhibitor of Human GAR Tfase: 10-(Trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic Acid^, Zhang, Yan; Desharnais, Joel; Marsilje, Thomas H. Biochemistry, Vol. 42, Issue 20 https://doi.org/10.1021/bi034219c	journal	May 2003
Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design Meanwell, Nicholas A. Journal of Medicinal Chemistry, Vol. 54, Issue 8 https://doi.org/10.1021/jm1013693	journal	April 2011
The Apo and Ternary Complex Structures of a Chemotherapeutic Target: Human Glycinamide Ribonucleotide Transformylase^, Dahms, Tanya E. S.; Sainz, Germaine; Giroux, Eugene L. Biochemistry, Vol. 44, Issue 29 https://doi.org/10.1021/bi050307g	journal	June 2005
Structural basis for molecular recognition of folic acid by folate receptors Chen, Chen; Ke, Jiyuan; Zhou, X. Edward Nature, Vol. 500, Issue 7463 https://doi.org/10.1038/nature12327	journal	July 2013
Isolation of Human cDNAs That Restore Methotrexate Sensitivity and Reduced Folate Carrier Activity in Methotrexate Transport-defective Chinese Hamster Ovary Cells Wong, So C.; Proefke, Susan A.; Bhushan, Alok Journal of Biological Chemistry, Vol. 270, Issue 29 https://doi.org/10.1074/jbc.270.29.17468	journal	July 1995
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^† Deng, Yijun; Zhou, Xilin; Kugel Desmoulin, Sita Journal of Medicinal Chemistry, Vol. 52, Issue 9 https://doi.org/10.1021/jm8011323	journal	April 2009
Isolation and partial characterization of three methotrexate-resistant phenotypes from Chinese hamster ovary cells Flintoff, Wayne F.; Davidson, Sandra V.; Siminovitch, Louis Somatic Cell Genetics, Vol. 2, Issue 3 https://doi.org/10.1007/BF01538963	journal	May 1976
Targeting the Proton-Coupled Folate Transporter for Selective Delivery of 6-Substituted Pyrrolo[2,3-d]Pyrimidine Antifolate Inhibitors of De Novo Purine Biosynthesis in the Chemotherapy of Solid Tumors Desmoulin, Sita Kugel; Wang, Yiqiang; Wu, Jianmei Molecular Pharmacology, Vol. 78, Issue 4 https://doi.org/10.1124/mol.110.065896	journal	July 2010
Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition Wibowo, A. S.; Singh, M.; Reeder, K. M. Proceedings of the National Academy of Sciences, Vol. 110, Issue 38 https://doi.org/10.1073/pnas.1308827110	journal	August 2013
Novel 5-Substituted Pyrrolo[2,3- d ]pyrimidines as Dual Inhibitors of Glycinamide Ribonucleotide Formyltransferase and 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase and as Potential Antitumor Agents Wang, Yiqiang; Mitchell-Ryan, Shermaine; Raghavan, Sudhir Journal of Medicinal Chemistry, Vol. 58, Issue 3 https://doi.org/10.1021/jm501787c	journal	February 2015
Molecular basis of antifolate resistance Assaraf, Yehuda G. Cancer and Metastasis Reviews, Vol. 26, Issue 1 https://doi.org/10.1007/s10555-007-9049-z	journal	February 2007
Presenting your structures: the CCP 4 mg molecular-graphics software McNicholas, S.; Potterton, E.; Wilson, K. S. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444911007281	journal	March 2011
Docking Validation Resources: Protein Family and Ligand Flexibility Experiments Mukherjee, Sudipto; Balius, Trent E.; Rizzo, Robert C. Journal of Chemical Information and Modeling, Vol. 50, Issue 11 https://doi.org/10.1021/ci1001982	journal	October 2010
DOCK 6: Impact of new features and current docking performance Allen, William J.; Balius, Trent E.; Mukherjee, Sudipto Journal of Computational Chemistry, Vol. 36, Issue 15 https://doi.org/10.1002/jcc.23905	journal	April 2015
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB Maier, James A.; Martinez, Carmenza; Kasavajhala, Koushik Journal of Chemical Theory and Computation, Vol. 11, Issue 8 https://doi.org/10.1021/acs.jctc.5b00255	journal	July 2015
UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
Functional Loss of the Reduced Folate Carrier Enhances the Antitumor Activities of Novel Antifolates with Selective Uptake by the Proton-Coupled Folate Transporter Desmoulin, Sita Kugel; Wang, Lei; Polin, Lisa Molecular Pharmacology, Vol. 82, Issue 4 https://doi.org/10.1124/mol.112.079004	journal	June 2012
Protein Measurement with the Folin Phenol Reagent Lowry, OliverH.; Rosebrough, NiraJ.; Farr, A. Lewis Journal of Biological Chemistry, Vol. 193, Issue 1 https://doi.org/10.1016/S0021-9258(19)52451-6	journal	November 1951
Conversion of Uracil Deoxyriboside to Thymidine of Deoxyribonucleic acid Friedkin, Morris; Roberts, DeWayne Journal of Biological Chemistry, Vol. 220, Issue 2 https://doi.org/10.1016/S0021-9258(18)65290-1	journal	June 1956
The Human Glycinamide Ribonucleotide Transformylase Domain: Purification, Characterization, and Kinetic Mechanism Caperelli, Carol A.; Giroux, Eugene L. Archives of Biochemistry and Biophysics, Vol. 341, Issue 1 https://doi.org/10.1006/abbi.1997.9947	journal	May 1997
Discovery of cryptophycin-1 and BCN-183577: Examples of strategies and problems in the detection of antitumor activity in mice Corbett, Thomas H.; Valeriote, Frederick A.; Demchik, Lisa Investigational New Drugs, Vol. 15, Issue 3 https://doi.org/10.1023/A:1005875015011	journal	September 1997
The Yeast HtrA Orthologue Ynm3 Is a Protease with Chaperone Activity that Aids Survival Under Heat Stress Padmanabhan, Nirmala; Fichtner, Lars; Dickmanns, Achim Molecular Biology of the Cell, Vol. 20, Issue 1 https://doi.org/10.1091/mbc.E08-02-0178	journal	January 2009
Transplantable Syngeneic Rodent Tumors: Solid Tumors in Mice Polin, Lisa; Corbett, Thomas H.; Roberts, Bill J. Tumor Models in Cancer Research https://doi.org/10.1007/978-1-60761-968-0_3	book	November 2010
Treatment of human prostate tumors PC-3 and TSU-PR1 with standard and investigational agents in SCID mice Polin, Lisa; Valeriote, Frederick; White, Kathryn Investigational New Drugs, Vol. 15, Issue 2 https://doi.org/10.1023/A:1005856605726	journal	June 1997
Long-Term Folate Deficiency Alters Folate Content and Distribution Differentially in Rat Tissues Varela-Moreiras, Gregorio; Selhub, Jacob The Journal of Nutrition, Vol. 122, Issue 4 https://doi.org/10.1093/jn/122.4.986	journal	April 1992
Recent developments in the PHENIX software for automated crystallographic structure determination Adams, Paul D.; Gopal, Kreshna; Grosse-Kunstleve, Ralf W. Journal of Synchrotron Radiation, Vol. 11, Issue 1 https://doi.org/10.1107/S0909049503024130	journal	November 2003
PHENIX : building new software for automated crystallographic structure determination Adams, Paul D.; Grosse-Kunstleve, Ralf W.; Hung, Li-Wei Acta Crystallographica Section D Biological Crystallography, Vol. 58, Issue 11 https://doi.org/10.1107/S0907444902016657	journal	October 2002
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard Terwilliger, Thomas C.; Grosse-Kunstleve, Ralf W.; Afonine, Pavel V. Acta Crystallographica Section D Biological Crystallography, Vol. 64, Issue 1 https://doi.org/10.1107/S090744490705024X	journal	December 2007
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
The CCP4 suite programs for protein crystallography Acta Crystallographica Section D Biological Crystallography, Vol. 50, Issue 5, p. 760-763 https://doi.org/10.1107/S0907444994003112	journal	September 1994
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997

Similar Records

A structural snapshot of the rhodopsin-arrestin complex

Journal Article · Sun Nov 01 00:00:00 EDT 2015 · Federation of European Biochemical Societies (FEBS) Journal · OSTI ID:1330265

Kang, Yanyong; Gao, Xiang; Zhou, X. Edward; +3 more

Structural basis for recognition of diverse transcriptional repressors by the TOPLESS family of corepressors

Journal Article · Fri Jul 03 00:00:00 EDT 2015 · Science Advances · OSTI ID:1330265

Ke, Jiyuan; Ma, Honglei; Gu, Xin; +5 more

Structural basis for corepressor assembly by the orphan nuclear receptor TLX

Journal Article · Sun Feb 15 00:00:00 EST 2015 · Genes & Development · OSTI ID:1330265

Zhi, Xiaoyong; Zhou, X. Edward; He, Yuanzheng; +5 more

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
nutrition
crystal structure
cells
inhibition
organic compounds

Title: Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

Citation Formats

References (68)

Similar Records

Related Subjects