Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues: Inhibition of inosine monophosphate dehydrogenase

Liqiang Chen; Riccardo Petrelli; Magdalena Olesiak; Daniel J. Wilson; Nicholas P. Labello; Krzysztof W. Pankiewicz

doi:10.1016/j.bmc.2008.06.003

Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues: Inhibition of inosine monophosphate dehydrogenase

Liqiang Chen, Riccardo Petrelli, Magdalena Olesiak, Daniel J. Wilson, Nicholas P. Labello, Krzysztof W. Pankiewicz

Center for Drug Design

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Abstract

Synthesis of novel inhibitors of human IMP dehydrogenase is described. These inhibitors are isosteric methylenebis(sulfonamide) analogues 5-8 of earlier reported mycophenolic adenine methylenebis(phosphonate)s 1-3. The parent bis(phosphonate) 1 and its bis(sulfonamide) analogue 5 showed similar sub-micromolar inhibitory activity against IMPDH2 (K_i ∼ 0.2 μM). However, the bis(sulfonamide) analogues 6 and 8 substituted at the position 2 of adenine were approximately 3- to 10-fold less potent inhibitors of IMPDH2 (K_i = 0.3-0.4 μM) than the corresponding parent bis(phosphonate)s 2 and 3 (K_i = 0.04-0.11μM), respectively.

Original language	English (US)
Pages (from-to)	7462-7469
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry
Volume	16
Issue number	15
DOIs	https://doi.org/10.1016/j.bmc.2008.06.003
State	Published - Aug 1 2008

Keywords

Inosine monophosphate dehydrogenase
Methylenebis(phoshonate)
Methylenebis(sulfonamide)
Mycophenolic acid
NAD analogues
Nicotinamide adenine dinucleotide

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title = "Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues: Inhibition of inosine monophosphate dehydrogenase",

abstract = "Synthesis of novel inhibitors of human IMP dehydrogenase is described. These inhibitors are isosteric methylenebis(sulfonamide) analogues 5-8 of earlier reported mycophenolic adenine methylenebis(phosphonate)s 1-3. The parent bis(phosphonate) 1 and its bis(sulfonamide) analogue 5 showed similar sub-micromolar inhibitory activity against IMPDH2 (Ki ∼ 0.2 μM). However, the bis(sulfonamide) analogues 6 and 8 substituted at the position 2 of adenine were approximately 3- to 10-fold less potent inhibitors of IMPDH2 (Ki = 0.3-0.4 μM) than the corresponding parent bis(phosphonate)s 2 and 3 (Ki = 0.04-0.11μM), respectively.",

keywords = "Inosine monophosphate dehydrogenase, Methylenebis(phoshonate), Methylenebis(sulfonamide), Mycophenolic acid, NAD analogues, Nicotinamide adenine dinucleotide",

author = "Liqiang Chen and Riccardo Petrelli and Magdalena Olesiak and Wilson, {Daniel J.} and Labello, {Nicholas P.} and Pankiewicz, {Krzysztof W.}",

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T1 - Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues

T2 - Inhibition of inosine monophosphate dehydrogenase

AU - Chen, Liqiang

AU - Petrelli, Riccardo

AU - Olesiak, Magdalena

AU - Wilson, Daniel J.

AU - Labello, Nicholas P.

AU - Pankiewicz, Krzysztof W.

PY - 2008/8/1

Y1 - 2008/8/1

N2 - Synthesis of novel inhibitors of human IMP dehydrogenase is described. These inhibitors are isosteric methylenebis(sulfonamide) analogues 5-8 of earlier reported mycophenolic adenine methylenebis(phosphonate)s 1-3. The parent bis(phosphonate) 1 and its bis(sulfonamide) analogue 5 showed similar sub-micromolar inhibitory activity against IMPDH2 (Ki ∼ 0.2 μM). However, the bis(sulfonamide) analogues 6 and 8 substituted at the position 2 of adenine were approximately 3- to 10-fold less potent inhibitors of IMPDH2 (Ki = 0.3-0.4 μM) than the corresponding parent bis(phosphonate)s 2 and 3 (Ki = 0.04-0.11μM), respectively.

AB - Synthesis of novel inhibitors of human IMP dehydrogenase is described. These inhibitors are isosteric methylenebis(sulfonamide) analogues 5-8 of earlier reported mycophenolic adenine methylenebis(phosphonate)s 1-3. The parent bis(phosphonate) 1 and its bis(sulfonamide) analogue 5 showed similar sub-micromolar inhibitory activity against IMPDH2 (Ki ∼ 0.2 μM). However, the bis(sulfonamide) analogues 6 and 8 substituted at the position 2 of adenine were approximately 3- to 10-fold less potent inhibitors of IMPDH2 (Ki = 0.3-0.4 μM) than the corresponding parent bis(phosphonate)s 2 and 3 (Ki = 0.04-0.11μM), respectively.

KW - Inosine monophosphate dehydrogenase

KW - Methylenebis(phoshonate)

KW - Methylenebis(sulfonamide)

KW - Mycophenolic acid

KW - NAD analogues

KW - Nicotinamide adenine dinucleotide

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U2 - 10.1016/j.bmc.2008.06.003

DO - 10.1016/j.bmc.2008.06.003

M3 - Article

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AN - SCOPUS:48449098290

SN - 0968-0896

VL - 16

SP - 7462

EP - 7469

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 15

ER -

Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues: Inhibition of inosine monophosphate dehydrogenase

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Keywords

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