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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

Abstract

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.

Authors:
 [1];  [2];  [3];  [3];  [4];  [4];  [1];  [5];  [1];  [6];  [4];  [6];  [6];  [2];  [6];  [7];  [4];  [3];  [6];  [1]
  1. Duquesne Univ., Pittsburgh, PA (United States)
  2. Barbara Ann Karmanos Cancer Inst., Detroit, MI (United States)
  3. Indiana Univ., Bloomington, IN (United States)
  4. Van Andel Research Inst., Grand Rapids, MI (United States)
  5. Wayne State Univ. School of Medicine, Detroit, MI (United States)
  6. Barbara Ann Karmanos Cancer Inst., Detroit, MI (United States); Wayne State Univ. School of Medicine, Detroit, MI (United States)
  7. Van Andel Research Inst., Grand Rapids, MI (United States); Chinese Academy of Sciences, Shanghai (China)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
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
OSTI Identifier:
1330265
Grant/Contract Number:  
AC02-06CH11357; 085P1000817; P30 CA022453; CA53535; CA125153; CA152316; CA166711; GM094472; DK071662; GM102545; GM104212; NSF91217311; 2012ZX09301001; 2012CB910403; 2013CB910600; XDB08020303; 2013ZX09507001
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 59; Journal Issue: 17; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; nutrition; crystal structure; cells; inhibition; organic compounds

Citation Formats

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., and Gangjee, Aleem. 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. United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.6b00594.
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. 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. United States. https://doi.org/10.1021/acs.jmedchem.6b00594
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., and Gangjee, Aleem. 2016. "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". United States. https://doi.org/10.1021/acs.jmedchem.6b00594. https://www.osti.gov/servlets/purl/1330265.
@article{osti_1330265,
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},
author = {Golani, Lalit K. and Wallace-Povirk, Adrianne and Deis, Siobhan M. and Wong, Jennifer and Ke, Jiyuan and Gu, Xin and Raghavan, Sudhir and Wilson, Mike R. and Li, Xinxin and Polin, Lisa and de Waal, Parker W. and White, Kathryn and Kushner, Juiwanna and O’Connor, Carrie and Hou, Zhanjun and Xu, H. Eric and Melcher, Karsten and Dann, III, Charles E. and Matherly, Larry H. and Gangjee, Aleem},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.6b00594},
url = {https://www.osti.gov/biblio/1330265}, journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 17,
volume = 59,
place = {United States},
year = {Tue Jul 26 00:00:00 EDT 2016},
month = {Tue Jul 26 00:00:00 EDT 2016}
}

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