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Title: Ferric ion-specific sequestering agents. 7. Synthesis, iron-exchange kinetics, and stability constants of N-substituted, sulfonated catechoylamide analogs of enterobactin

Abstract

For treatment of chronic iron overload (as occurs in Cooley's anemia), ferric ion sequestering agents with specific properties are necessary. Two analogues of enterobactin [a microbial chelating agent with the greatest stability constant known for an Fe(III) complex] are reported which exhibit: i) hydrolytic stability; ii) water solubility; iii) N-substitution to block peptidase hydrolysis. The first compound, N,N',N"- trimethyl-N,N',N"-tris(2,3-dihydroxysulfobenzoyl)1,3,5-triaminomethyl- benzene, [Me 3MECAMS, 6] was prepared from the amide of trimesloyl chloride (1) and MeNH 2. The resulting amide was reduced to the triamine (3) and converted in three steps to the final product 6 in 6% overall yield. The proton-dependent formation constant (log K*) for the reaction: Fe 3+ + H 3L 6- = FeL 6- + 3H + is 4.87, which gives an equilibrium concentration of [Fe 3+] at pH 7.4 of 2 x 10 -27 M for 10 -5 M L (6) and 10 -6 M total Fe 3+. The estimated formation constant (log β 110) is 40. At low pH the FeL 6- complex undergoes a series of three, one-proton reactions which probably gives a tris-salicylate complex formed by the carbonyl and ortho-catechol oxygen of the 2,3-dihydroxybenzoyl units (the same reaction that occurs with ferric enterobactin). Aftermore » six hours in the presence of 6 mM ascorbate, Me 3MECAMS (6.0 mM) removed 3.7% of the ferric ion initially sequestered by the iron storage protein, ferritin. The human iron transport protein transferrin gives up iron to Me 3MECAMS with a pseudo first-order rate constant of 1.9 x 10 -3min -1 (ligand concentration 2 X 10 -4 M). This rate is comparable to that of enterobactin and other catechoyl amide sequestering agents, and greatly exceeds that of desferrioxamine B (Desferal®), the current drug of choice in treating iron overload. Two related compounds have been prepared in which the catechol ring is attached to the amide nitrogen through a methylene group, with amide formation with an acetyl group. In N,N',N"-triacetyl-N,N' ,N"-tris(2,3-dihydroxysulfobenzoyl)-N,N',N"-triaminomethylbenzene [NAcMECAMS, 111... and its unsulfonated precursor, the amide linkage of the catechoyl amides such as Me 3MECAMS (6) has been shifted from an endo position relative to the benzene and catechol rings to an exo position in which the amide carbonyl is not conjugated with the catechol ring and cannot form a stable chelate ring in conjunction with a catechol oxygen. The preparation of 11 and 10 proceeded from the previously described precursor of TRIMCAM, 7, borane reduction to the triamine 8, and amide formation with acetyl chloride to 9, followed by deprotection of the catechol oxygens with BBr 3/CH 2Cl 2 to give 10. Sulfonation of 10 to NAcMECAMS, 11, is carried out in fuming sulfuric acid. In comparison with Me 3MECAMS, the protonation of NAcMECAMS (11) proceeds by an initial two-proton step in contrast to the one-proton reactions typical of the catechoyl amides, which can form a salicylate mode of coordination involving the amide carbonyl group. In addition, as a result of the removal of the carbonyl group from conjugation with the catechol ring, the acidity of NAcMECAMS (11) is less than Me 3MECAMS (6). While the estimated log β 110 is approximately the same as for Me 3MECAMS (40), the effective formation constant (log K*) and pM.(- log [Fe aq 3+]) values are lower (4.0 and 25.0, respectively).« less

Authors:
 [1];  [1];  [1]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1108740
Report Number(s):
LBL-11807
Journal ID: ISSN 0002-7863
DOE Contract Number:  
AC02-05CH11231; W-7405-ENG-48
Resource Type:
Journal Article
Journal Name:
Journal of the American Chemical Society
Additional Journal Information:
Journal Volume: 103; Journal Issue: 17; Journal ID: ISSN 0002-7863
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Pecoraro, Vincent L., Weit, Frederick L., and Raymond, Kenneth N. Ferric ion-specific sequestering agents. 7. Synthesis, iron-exchange kinetics, and stability constants of N-substituted, sulfonated catechoylamide analogs of enterobactin. United States: N. p., 1981. Web. doi:10.1021/ja00407a030.
Pecoraro, Vincent L., Weit, Frederick L., & Raymond, Kenneth N. Ferric ion-specific sequestering agents. 7. Synthesis, iron-exchange kinetics, and stability constants of N-substituted, sulfonated catechoylamide analogs of enterobactin. United States. doi:10.1021/ja00407a030.
Pecoraro, Vincent L., Weit, Frederick L., and Raymond, Kenneth N. Sat . "Ferric ion-specific sequestering agents. 7. Synthesis, iron-exchange kinetics, and stability constants of N-substituted, sulfonated catechoylamide analogs of enterobactin". United States. doi:10.1021/ja00407a030. https://www.osti.gov/servlets/purl/1108740.
@article{osti_1108740,
title = {Ferric ion-specific sequestering agents. 7. Synthesis, iron-exchange kinetics, and stability constants of N-substituted, sulfonated catechoylamide analogs of enterobactin},
author = {Pecoraro, Vincent L. and Weit, Frederick L. and Raymond, Kenneth N.},
abstractNote = {For treatment of chronic iron overload (as occurs in Cooley's anemia), ferric ion sequestering agents with specific properties are necessary. Two analogues of enterobactin [a microbial chelating agent with the greatest stability constant known for an Fe(III) complex] are reported which exhibit: i) hydrolytic stability; ii) water solubility; iii) N-substitution to block peptidase hydrolysis. The first compound, N,N',N"- trimethyl-N,N',N"-tris(2,3-dihydroxysulfobenzoyl)1,3,5-triaminomethyl- benzene, [Me3MECAMS, 6] was prepared from the amide of trimesloyl chloride (1) and MeNH2. The resulting amide was reduced to the triamine (3) and converted in three steps to the final product 6 in 6% overall yield. The proton-dependent formation constant (log K*) for the reaction: Fe3+ + H3L6- = FeL6- + 3H+ is 4.87, which gives an equilibrium concentration of [Fe3+] at pH 7.4 of 2 x 10-27 M for 10-5 M L (6) and 10-6 M total Fe3+. The estimated formation constant (log β110) is 40. At low pH the FeL6- complex undergoes a series of three, one-proton reactions which probably gives a tris-salicylate complex formed by the carbonyl and ortho-catechol oxygen of the 2,3-dihydroxybenzoyl units (the same reaction that occurs with ferric enterobactin). After six hours in the presence of 6 mM ascorbate, Me3MECAMS (6.0 mM) removed 3.7% of the ferric ion initially sequestered by the iron storage protein, ferritin. The human iron transport protein transferrin gives up iron to Me3MECAMS with a pseudo first-order rate constant of 1.9 x 10-3min-1 (ligand concentration 2 X 10-4 M). This rate is comparable to that of enterobactin and other catechoyl amide sequestering agents, and greatly exceeds that of desferrioxamine B (Desferal®), the current drug of choice in treating iron overload. Two related compounds have been prepared in which the catechol ring is attached to the amide nitrogen through a methylene group, with amide formation with an acetyl group. In N,N',N"-triacetyl-N,N' ,N"-tris(2,3-dihydroxysulfobenzoyl)-N,N',N"-triaminomethylbenzene [NAcMECAMS, 111... and its unsulfonated precursor, the amide linkage of the catechoyl amides such as Me3MECAMS (6) has been shifted from an endo position relative to the benzene and catechol rings to an exo position in which the amide carbonyl is not conjugated with the catechol ring and cannot form a stable chelate ring in conjunction with a catechol oxygen. The preparation of 11 and 10 proceeded from the previously described precursor of TRIMCAM, 7, borane reduction to the triamine 8, and amide formation with acetyl chloride to 9, followed by deprotection of the catechol oxygens with BBr3/CH2Cl2 to give 10. Sulfonation of 10 to NAcMECAMS, 11, is carried out in fuming sulfuric acid. In comparison with Me3MECAMS, the protonation of NAcMECAMS (11) proceeds by an initial two-proton step in contrast to the one-proton reactions typical of the catechoyl amides, which can form a salicylate mode of coordination involving the amide carbonyl group. In addition, as a result of the removal of the carbonyl group from conjugation with the catechol ring, the acidity of NAcMECAMS (11) is less than Me3MECAMS (6). While the estimated log β110 is approximately the same as for Me3MECAMS (40), the effective formation constant (log K*) and pM.(- log [Feaq3+]) values are lower (4.0 and 25.0, respectively).},
doi = {10.1021/ja00407a030},
journal = {Journal of the American Chemical Society},
issn = {0002-7863},
number = 17,
volume = 103,
place = {United States},
year = {1981},
month = {8}
}