期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 20, 期 19, 页码 5915-5927出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.07.047
关键词
Acute lymphoblastic leukemia; Asparagine synthetase; Transition-state analogue inhibitor; Sulfoximine; Structure-activity relationship; MOLT-4 leukemia cell line; L-Asparagine amidohydrolase; Cell death
资金
- Japan Society for the Promotion of Science [23510278]
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- University of Florida
- National Institutes of Health (National Center for Research Resources) [2P41RR001081]
- National Institutes of Health (National Institute of General Medical Sciences) [9P41GM103311]
- Grants-in-Aid for Scientific Research [23510278] Funding Source: KAKEN
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 (IC50 = 0.1 mM). 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. (C) 2012 Elsevier Ltd. All rights reserved.
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