Abstract
Ethacrynic acid, a clinically useful diuretic, has been shown to inhibit l-asparagine synthetase from leukemia 5178Y resistant to l-asparaginase (L5178Y/AR) in vitro. This inhibition is thought to involve the formation of an adduct between ethacrynic acid and sulfhydryl functions on the enzyme; the adduct is not readily reversible even when another thiol, such as dithiothreitol, is used to displace the acid. A series of analogs of ethacrynic acid were examined as inhibitors of l-asparagine synthetase. Only one proved to be superior to the title compound; it was 2 2-(1-carboxymethoxy-4-chloro-2-naphthyl)3,6-diethyl-6-(1-carboxymethoxy- 4-chloro-2-naphthoyl)-5,6-dihydro-[4H]-pyran (Compound D). There was no correlation between the diuretic or natriuretic potency of the series of compounds examined and their ability to inhibit l-asparagine synthetase activity. There was also no correlation between the ability of these agents to inhibit l-asparaginase from Dasyprocta agouti (another sulfhydryl enzyme) and l-asparagine synthetase from L5178Y/AR. In every case, ethacrynic acid and its analogs interrupted the utilization of ammonia by l-asparagine synthetase to a greater degree than the utilization of l-glutamine. In vivo, the inhibition by l-asparagine synthetase from L5178Y/AR by ethacrynic acid was feeble, while the analogous enzyme from pancreas was inhibited to a significant degree.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1787-1792 |
| Number of pages | 6 |
| Journal | Biochemical Pharmacology |
| Volume | 24 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 1 1975 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Pharmacology
Cite this
Ethacrynic acid-an inhibitor of l-asparagine synthetase. / Jayaram, Hiremagalur N.; Cooney, David A.; Milman, Harry A.; Homan, Elton R.; King, Valarie M.; Cragoe, Edward J.
In: Biochemical Pharmacology, Vol. 24, No. 19, 01.10.1975, p. 1787-1792.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ethacrynic acid-an inhibitor of l-asparagine synthetase
AU - Jayaram, Hiremagalur N.
AU - Cooney, David A.
AU - Milman, Harry A.
AU - Homan, Elton R.
AU - King, Valarie M.
AU - Cragoe, Edward J.
PY - 1975/10/1
Y1 - 1975/10/1
N2 - Ethacrynic acid, a clinically useful diuretic, has been shown to inhibit l-asparagine synthetase from leukemia 5178Y resistant to l-asparaginase (L5178Y/AR) in vitro. This inhibition is thought to involve the formation of an adduct between ethacrynic acid and sulfhydryl functions on the enzyme; the adduct is not readily reversible even when another thiol, such as dithiothreitol, is used to displace the acid. A series of analogs of ethacrynic acid were examined as inhibitors of l-asparagine synthetase. Only one proved to be superior to the title compound; it was 2 2-(1-carboxymethoxy-4-chloro-2-naphthyl)3,6-diethyl-6-(1-carboxymethoxy- 4-chloro-2-naphthoyl)-5,6-dihydro-[4H]-pyran (Compound D). There was no correlation between the diuretic or natriuretic potency of the series of compounds examined and their ability to inhibit l-asparagine synthetase activity. There was also no correlation between the ability of these agents to inhibit l-asparaginase from Dasyprocta agouti (another sulfhydryl enzyme) and l-asparagine synthetase from L5178Y/AR. In every case, ethacrynic acid and its analogs interrupted the utilization of ammonia by l-asparagine synthetase to a greater degree than the utilization of l-glutamine. In vivo, the inhibition by l-asparagine synthetase from L5178Y/AR by ethacrynic acid was feeble, while the analogous enzyme from pancreas was inhibited to a significant degree.
AB - Ethacrynic acid, a clinically useful diuretic, has been shown to inhibit l-asparagine synthetase from leukemia 5178Y resistant to l-asparaginase (L5178Y/AR) in vitro. This inhibition is thought to involve the formation of an adduct between ethacrynic acid and sulfhydryl functions on the enzyme; the adduct is not readily reversible even when another thiol, such as dithiothreitol, is used to displace the acid. A series of analogs of ethacrynic acid were examined as inhibitors of l-asparagine synthetase. Only one proved to be superior to the title compound; it was 2 2-(1-carboxymethoxy-4-chloro-2-naphthyl)3,6-diethyl-6-(1-carboxymethoxy- 4-chloro-2-naphthoyl)-5,6-dihydro-[4H]-pyran (Compound D). There was no correlation between the diuretic or natriuretic potency of the series of compounds examined and their ability to inhibit l-asparagine synthetase activity. There was also no correlation between the ability of these agents to inhibit l-asparaginase from Dasyprocta agouti (another sulfhydryl enzyme) and l-asparagine synthetase from L5178Y/AR. In every case, ethacrynic acid and its analogs interrupted the utilization of ammonia by l-asparagine synthetase to a greater degree than the utilization of l-glutamine. In vivo, the inhibition by l-asparagine synthetase from L5178Y/AR by ethacrynic acid was feeble, while the analogous enzyme from pancreas was inhibited to a significant degree.
UR - http://www.scopus.com/inward/record.url?scp=0016723291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0016723291&partnerID=8YFLogxK
U2 - 10.1016/0006-2952(75)90458-X
DO - 10.1016/0006-2952(75)90458-X
M3 - Article
C2 - 9943
AN - SCOPUS:0016723291
VL - 24
SP - 1787
EP - 1792
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 19
ER -