Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway

Heng Cheng; Inkyu Hwang; Youhoon Chong; Ali Tavassoli; Michael E. Webb; Yan Zhang; Ian A. Wilson; Stephen J. Benkovic; Dale L. Boger

doi:10.1016/j.bmc.2004.11.049

Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway

Heng Cheng, Inkyu Hwang, Youhoon Chong, Ali Tavassoli, Michael E. Webb, Yan Zhang, Ian A. Wilson, Stephen J. Benkovic, Dale L. Boger

Chemistry

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

The synthesis and evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-l-glutamic acid (2) as an inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The inhibitor 2 was prepared in a convergent synthesis involving C-alkylation of methyl 4-(4,4,4-trifluoro-3-dimethylhydrazonobutyl)benzoate with 1-chloro-3-iodopropane followed by construction of the pyrimidinone ring. Compound 2 was found to be an effective inhibitor of recombinant human GAR Tfase (K_i = 0.50 μM), whereas it was inactive (K_i > 100 μM) against E. coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC₅₀ = 6.0 μM).

Original language	English (US)
Pages (from-to)	3593-3599
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	13
Issue number	10
DOIs	https://doi.org/10.1016/j.bmc.2004.11.049
State	Published - May 15 2005

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmc.2004.11.049

Fingerprint

Dive into the research topics of 'Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway'. Together they form a unique fingerprint.

Cite this

Cheng, H., Hwang, I., Chong, Y., Tavassoli, A., Webb, M. E., Zhang, Y., Wilson, I. A., Benkovic, S. J., & Boger, D. L. (2005). Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway. Bioorganic and Medicinal Chemistry, 13(10), 3593-3599. https://doi.org/10.1016/j.bmc.2004.11.049

@article{f820abc28e874a1d85ca120c51da96a4,

title = "Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway",

abstract = "The synthesis and evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-l-glutamic acid (2) as an inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The inhibitor 2 was prepared in a convergent synthesis involving C-alkylation of methyl 4-(4,4,4-trifluoro-3-dimethylhydrazonobutyl)benzoate with 1-chloro-3-iodopropane followed by construction of the pyrimidinone ring. Compound 2 was found to be an effective inhibitor of recombinant human GAR Tfase (Ki = 0.50 μM), whereas it was inactive (Ki > 100 μM) against E. coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC50 = 6.0 μM).",

author = "Heng Cheng and Inkyu Hwang and Youhoon Chong and Ali Tavassoli and Webb, {Michael E.} and Yan Zhang and Wilson, {Ian A.} and Benkovic, {Stephen J.} and Boger, {Dale L.}",

note = "Funding Information: We gratefully acknowledge the financial support of the National Institute of Health (CA 63536, to D.L.B., I.A.W., and S.J.B.), and the Skaggs Institute for Chemical Biology. Y.Z. is a Skaggs Fellow.",

year = "2005",

month = may,

day = "15",

doi = "10.1016/j.bmc.2004.11.049",

language = "English (US)",

volume = "13",

pages = "3593--3599",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Limited",

number = "10",

}

Cheng, H, Hwang, I, Chong, Y, Tavassoli, A, Webb, ME, Zhang, Y, Wilson, IA, Benkovic, SJ & Boger, DL 2005, 'Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway', Bioorganic and Medicinal Chemistry, vol. 13, no. 10, pp. 3593-3599. https://doi.org/10.1016/j.bmc.2004.11.049

Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway. / Cheng, Heng; Hwang, Inkyu; Chong, Youhoon et al.
In: Bioorganic and Medicinal Chemistry, Vol. 13, No. 10, 15.05.2005, p. 3593-3599.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway

AU - Cheng, Heng

AU - Hwang, Inkyu

AU - Chong, Youhoon

AU - Tavassoli, Ali

AU - Webb, Michael E.

AU - Zhang, Yan

AU - Wilson, Ian A.

AU - Benkovic, Stephen J.

AU - Boger, Dale L.

N1 - Funding Information: We gratefully acknowledge the financial support of the National Institute of Health (CA 63536, to D.L.B., I.A.W., and S.J.B.), and the Skaggs Institute for Chemical Biology. Y.Z. is a Skaggs Fellow.

PY - 2005/5/15

Y1 - 2005/5/15

N2 - The synthesis and evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-l-glutamic acid (2) as an inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The inhibitor 2 was prepared in a convergent synthesis involving C-alkylation of methyl 4-(4,4,4-trifluoro-3-dimethylhydrazonobutyl)benzoate with 1-chloro-3-iodopropane followed by construction of the pyrimidinone ring. Compound 2 was found to be an effective inhibitor of recombinant human GAR Tfase (Ki = 0.50 μM), whereas it was inactive (Ki > 100 μM) against E. coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC50 = 6.0 μM).

AB - The synthesis and evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-l-glutamic acid (2) as an inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The inhibitor 2 was prepared in a convergent synthesis involving C-alkylation of methyl 4-(4,4,4-trifluoro-3-dimethylhydrazonobutyl)benzoate with 1-chloro-3-iodopropane followed by construction of the pyrimidinone ring. Compound 2 was found to be an effective inhibitor of recombinant human GAR Tfase (Ki = 0.50 μM), whereas it was inactive (Ki > 100 μM) against E. coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC50 = 6.0 μM).

UR - http://www.scopus.com/inward/record.url?scp=17444418621&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=17444418621&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2004.11.049

DO - 10.1016/j.bmc.2004.11.049

M3 - Article

C2 - 15848772

AN - SCOPUS:17444418621

SN - 0968-0896

VL - 13

SP - 3593

EP - 3599

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 10

ER -

Cheng H, Hwang I, Chong Y, Tavassoli A, Webb ME, Zhang Y et al. Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway. Bioorganic and Medicinal Chemistry. 2005 May 15;13(10):3593-3599. doi: 10.1016/j.bmc.2004.11.049

Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this