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
Organic Chemistry
Clinical Biochemistry

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10.1016/j.bmc.2004.12.004

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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",

journal = "Bioorganic and Medicinal Chemistry",

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number = "10",

}

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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UR - https://www.scopus.com/pages/publications/17444399660#tab=citedBy

U2 - 10.1016/j.bmc.2004.12.004

DO - 10.1016/j.bmc.2004.12.004

M3 - Article

C2 - 15848770

AN - SCOPUS:17444399660

SN - 0968-0896

VL - 13

SP - 3577

EP - 3585

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 10

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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