ACS Medicinal Chemistry Letters
). Toward that end, we prepared 20ꢀ22 from the correspondꢀ
Page 4 of 6
1
This work was supported by the fund from the Department of
Anesthesia, Critical Care and Pain Medicine at Massachusetts
General Hospital (WMZ), NIH/NIMHD grant MD009124 (MKS).
Structural biology resources were provided in part by NIH grant
CA16059 to the VCU Massey Cancer Center.
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9
1
1
1
1
1
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1
1
1
2
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2
2
2
2
2
2
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ing boronates and boronic acid for 20 and 21, and for 22, reꢀ
spectively (Scheme 1). Dimethylaminomethyl analog 22 was
obtained by reductive amination of aldehyde 13 obtained using
5
ꢀformylfuranꢀ2ꢀboronic acid as a coupling partner.
Both hydroxymethyl isoxazole 21 and dimethylaꢀ
Notes
minomethylfuran 22 were significantly more active to reduce
COHb halfꢀlife than 2 at 5:1 molar ratio of the compound to
Hb tetramer. COHb halfꢀlife lowering activity with 21 was
comparable to that of 1, but without hemolytic activity at up to
Previously published academic dissertation available online:
Goldstein, Sara R, "The Design and Synthesis of Allosteric Effecꢀ
tors of Carbon Monoxide Binding to Hemoglobin"
(2017). Dissertations available from ProQuest. AAI10255227.
5
x the concentration of the compound to Hb tetramer. Furꢀ
0
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thermore, 21 exhibited superior aqueous solubility, making it
an excellent candidate for further study.
ACKNOWLEDGMENT
Our results establish a delicate balance between hydroꢀ
philicity that is adequate to improve aqueous solubility and
preclude hemolysis, as well as sufficient hydrophobicity for
sufficient biological activity. We pursued compounds modiꢀ
fied at the 4ꢀposition of the C ring, adding heteroaromatic
rings that aid in solubility while retaining the hydrophobic
surface area that appears necessary to reduce the halfꢀlife of
COHb. Five of the biaryl analogs, biphenyl 15, furan 16, isoxꢀ
azole 18, alcohol 21 and dimethyaminomethylfuran 22, led to
reduced COHb halfꢀlife relative to that observed with 1. We
were particularly gratified to find that COHb halfꢀlife was
significantly reduced with 21 relative to 2, without hemolysis.
These results demonstrate that it is possible to reduce the halfꢀ
life COHb with small molecules, a first step towards the use of
small molecules for the treatment of CO poisoning. The comꢀ
bination of these IRL compounds and compounds targeting the
extraꢀhemoglobin effects could have synergetic effects in
treating myocardial injury and the delay of CNS impairment
following CO poisoning. Further studies directed toward the
expansion of the SAR of the IRL compounds, the effect of
cLogP on hemolysis and the development of such compounds
is underway in our laboratory and our results will be reported
in due course.
We would like to acknowledge the Department of Anesthesia,
Critical Care and Pain Medicine at Massachusetts General Hospiꢀ
tal (WMZ), the NIH/NIMHD (MKS), NIH (MKS) for funding.
We would also like to acknowledge Dr. George Furst and Dr. Jun
Gu for NMR facility support and Dr. Rakesh Kohli and Dr.
Charles Ross for mass spectrometry services at the University of
Pennsylvania.
ABBREVIATIONS
CO, carbon monoxide; COHb, carboxyhemoglobin; DPG, 2,3ꢀ
diphosphoglycerate; Hb, hemoglobin; O , oxygen; ODC, oxygen
dissociation curve; RBC, red blood cells.
2
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*Eꢀmail: winkler@sas.upenn.edu.
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ORCID
Sara R. Goldstein: 0000ꢀ0002ꢀ7827ꢀ1404
Martin K. Safo: 0000ꢀ0002ꢀ9536ꢀ1743
Akito Nakagawa: 0000ꢀ0002ꢀ7047ꢀ1735
2
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(
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Dane, S,; Akyol, O. The role of reactive oxygen species and oxidative
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Report, 2014, 19 (5), 180ꢀ189.
SRG, CL, AN, WMZ, and JDW conceived the study and planned
the experiments. SRG, CL, and MKS carried out the experiments
and analyzed the data. The manuscript was written through conꢀ
tributions of all authors. All authors have given approval to the
final version of the manuscript.
(
14) Satran, D.; Henry, C. R.; Adkinson, C.; Nicholson, C. I.; Bracha,
Y.; Henry, T. D. Cardiovascular manifestations of moderate to severe
carbon monoxide poisoning. J Am Coll Cardiol. 2005, 45 (9). 1513ꢀ
1516.
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