A sulfoximine-based inhibitor of human asparagine synthetase kills L-asparaginase-resistant leukemia cells.

Abstract

An adenylated sulfoximine transition-state analogue 1, which inhibits human asparagine synthetase (hASNS) with nanomolar potency, has been reported to suppress the proliferation of an l-asparagine amidohydrolase (ASNase)-resistant MOLT-4 leukemia cell line (MOLT-4R) when l-asparagine is depleted in the medium. We now report the synthesis and biological activity of two new sulfoximine analogues of 1 that have been studied as part of systematic efforts to identify compounds with improved cell permeability and/or metabolic stability. One of these new analogues, an amino sulfoximine 5 having no net charge at cellular pH, is a better hASNS inhibitor (K(I)(∗)=8 nM) than 1 and suppresses proliferation of MOLT-4R cells at 10-fold lower concentration (IC(50)=0.1mM). More importantly, and in contrast to the lead compound 1, the presence of sulfoximine 5 at concentrations above 0.25 mM causes the death of MOLT-4R cells even when ASNase is absent in the culture medium. The amino sulfoximine 5 exhibits different dose-response behavior when incubated with an ASNase-sensitive MOLT-4 cell line (MOLT-4S), supporting the hypothesis that sulfoximine 5 exerts its effect by inhibiting hASNS in the cell. Our work provides further evidence for the idea that hASNS represents a chemotherapeutic target for the treatment of leukemia, and perhaps other cancers, including those of the prostate.

• Authors: Hideyuki Ikeuchi, Yong-Mo Ahn, Takuya Otokawa, Bunta Watanabe, Lamees Hegazy, Jun Hiratake, Nigel G J Richards
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 19 Pg. 5915-27 (Oct 01 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22951255 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Imines
• Sulfur Compounds
• Asparagine
• Amidohydrolases
• N-terminal asparagine amidohydrolase
• Asparaginase
• Aspartate-Ammonia Ligase

Topics

• Amidohydrolases (metabolism)
• Antineoplastic Agents (chemistry, pharmacology)
• Asparaginase (metabolism)
• Asparagine (metabolism)
• Aspartate-Ammonia Ligase (antagonists & inhibitors, metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Imines (chemistry, pharmacology)
• Models, Molecular
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, enzymology)
• Sulfur Compounds (chemistry, pharmacology)