Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway

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

doi:10.1016/j.bmc.2004.12.004

Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway

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

Chemistry

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

4 Scopus citations

Abstract

The synthesis and evaluation of 10-methanesulfonyl-DDACTHF (1), 10-methanesulfonyl-5-DACTHF (2), and 10-methylthio-DDACTHF (3) as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The compounds 10-methanesulfonyl-DDACTHF (1, K_i = 0.23 μM), 10-methanesulfonyl-5-DACTHF (2, K_i = 0.58 μM), and 10-methylthio-DDACTHF (3, K_i = 0.25 μM) were found to be selective and potent inhibitors of recombinant human GAR Tfase. Of these, 3 exhibited exceptionally potent, purine sensitive growth inhibition activity (3, IC ₅₀ = 100 nM) against the CCRF-CEM cell line being 3-fold more potent than Lometrexol and 30-fold more potent than the parent, unsubstituted DDACTHF, whereas 1 and 2 exhibited more modest growth inhibition activity (1, IC ₅₀ = 1.0 μM and 2, IC₅₀ = 2.0 μM).

Original language	English (US)
Pages (from-to)	3577-3585
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	13
Issue number	10
DOIs	https://doi.org/10.1016/j.bmc.2004.12.004
State	Published - May 15 2005

All Science Journal Classification (ASJC) codes

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

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Cheng, H., Chong, Y., Hwang, I., Tavassoli, A., Zhang, Y., Wilson, I. A., Benkovic, S. J., & Boger, D. L. (2005). Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway. Bioorganic and Medicinal Chemistry, 13(10), 3577-3585. https://doi.org/10.1016/j.bmc.2004.12.004

@article{c63bc8b070754f379017e675ad2c03fd,

title = "Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway",

abstract = "The synthesis and evaluation of 10-methanesulfonyl-DDACTHF (1), 10-methanesulfonyl-5-DACTHF (2), and 10-methylthio-DDACTHF (3) as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The compounds 10-methanesulfonyl-DDACTHF (1, Ki = 0.23 μM), 10-methanesulfonyl-5-DACTHF (2, Ki = 0.58 μM), and 10-methylthio-DDACTHF (3, Ki = 0.25 μM) were found to be selective and potent inhibitors of recombinant human GAR Tfase. Of these, 3 exhibited exceptionally potent, purine sensitive growth inhibition activity (3, IC 50 = 100 nM) against the CCRF-CEM cell line being 3-fold more potent than Lometrexol and 30-fold more potent than the parent, unsubstituted DDACTHF, whereas 1 and 2 exhibited more modest growth inhibition activity (1, IC 50 = 1.0 μM and 2, IC50 = 2.0 μM).",

author = "Heng Cheng and Youhoon Chong and Inkyu Hwang and Ali Tavassoli 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.2004.12.004",

language = "English (US)",

volume = "13",

pages = "3577--3585",

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Cheng, H, Chong, Y, Hwang, I, Tavassoli, A, Zhang, Y, Wilson, IA, Benkovic, SJ & Boger, DL 2005, 'Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway', Bioorganic and Medicinal Chemistry, vol. 13, no. 10, pp. 3577-3585. https://doi.org/10.1016/j.bmc.2004.12.004

Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway. / Cheng, Heng; Chong, Youhoon; Hwang, Inkyu et al.
In: Bioorganic and Medicinal Chemistry, Vol. 13, No. 10, 15.05.2005, p. 3577-3585.

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

TY - JOUR

T1 - Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway

AU - Cheng, Heng

AU - Chong, Youhoon

AU - Hwang, Inkyu

AU - Tavassoli, Ali

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 10-methanesulfonyl-DDACTHF (1), 10-methanesulfonyl-5-DACTHF (2), and 10-methylthio-DDACTHF (3) as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The compounds 10-methanesulfonyl-DDACTHF (1, Ki = 0.23 μM), 10-methanesulfonyl-5-DACTHF (2, Ki = 0.58 μM), and 10-methylthio-DDACTHF (3, Ki = 0.25 μM) were found to be selective and potent inhibitors of recombinant human GAR Tfase. Of these, 3 exhibited exceptionally potent, purine sensitive growth inhibition activity (3, IC 50 = 100 nM) against the CCRF-CEM cell line being 3-fold more potent than Lometrexol and 30-fold more potent than the parent, unsubstituted DDACTHF, whereas 1 and 2 exhibited more modest growth inhibition activity (1, IC 50 = 1.0 μM and 2, IC50 = 2.0 μM).

AB - The synthesis and evaluation of 10-methanesulfonyl-DDACTHF (1), 10-methanesulfonyl-5-DACTHF (2), and 10-methylthio-DDACTHF (3) as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The compounds 10-methanesulfonyl-DDACTHF (1, Ki = 0.23 μM), 10-methanesulfonyl-5-DACTHF (2, Ki = 0.58 μM), and 10-methylthio-DDACTHF (3, Ki = 0.25 μM) were found to be selective and potent inhibitors of recombinant human GAR Tfase. Of these, 3 exhibited exceptionally potent, purine sensitive growth inhibition activity (3, IC 50 = 100 nM) against the CCRF-CEM cell line being 3-fold more potent than Lometrexol and 30-fold more potent than the parent, unsubstituted DDACTHF, whereas 1 and 2 exhibited more modest growth inhibition activity (1, IC 50 = 1.0 μM and 2, IC50 = 2.0 μM).

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M3 - Article

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SN - 0968-0896

VL - 13

SP - 3577

EP - 3585

JO - Bioorganic and Medicinal Chemistry

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ER -

Cheng H, Chong Y, Hwang I, Tavassoli A, Zhang Y, Wilson IA et al. Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway. Bioorganic and Medicinal Chemistry. 2005 May 15;13(10):3577-3585. doi: 10.1016/j.bmc.2004.12.004

Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway

Abstract

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