Bioactive properties of iron-containing carbon monoxide-releasing molecules

P  Sawle; J  Hammad; I J S  Fairlamb; B  Moulton; C T  O'Brien; J M  Lynam; A K  Duhme-Klair; R  Foresti; R  Motterlini

doi:10.1124/jpet.106.101758

Bioactive properties of iron-containing carbon monoxide-releasing molecules

P Sawle, J Hammad, I J S Fairlamb, B Moulton, C T O'Brien, J M Lynam, A K Duhme-Klair, R Foresti, R Motterlini

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Carbon monoxide-releasing molecules (CO-RMs) are compounds capable of delivering controlled amounts of CO within a cellular environment. Ruthenium-based carbonyls [tricarbonyldichloro ruthenium(II) dimer and tricarbonylchloro(glycinato) ruthenium(II)] and boronacorbonates (sodium boranocarbonate) have been shown to promote vasodilatory, cardioprotective, and anti-inflammatory activities in a variety of experimental models. Here, we extend our previous studies by showing that eta-4-(4-bromo-6-methyl-2-pyrone) tricarbonyl iron (0) (CORM-F3), an irontricarbonyl complex that contains a 2-pyrone motif, liberates CO in vitro and exerts pharmacological actions that are typical of CO gas. Specifically, CORM-F3 caused vasorelaxation in isolated aortic rings and inhibited the inflammatory response (e.g., nitrite production) of RAW264.7 macrophages stimulated with endotoxin in a dose-dependent fashion. By analyzing the rate of CO release, we found that when the bromide at the 4-position of the 2-pyrone CORM-F3 is substituted with a chloride group [eta-4-(4-chloro-6-methyl-2pyrone) tricarbonyl iron (0) (CORM-F8)], the rate of CO release is significantly decreased (4.5-fold), and a further decrease is observed when the 4- and 6-positions are substituted with a methyl group [eta-4-(4-methyl-6-methyl-2-pyrone) tricarbonyl iron (0) CORM-F11)] or a hydrogen [eta-4-(4-chloro-2-pyrone) tricarbonyl iron (0) CORM-F7)], respectively. Interestingly, the compounds containing halogens at the 4- position and the methyl at the 6-position of the 2-pyrone ring (CORM-F3 and CORM-F8) were found to be less cytotoxic compared with other CO-RMs when tested in RAW246.7 macrophages. Thus, iron-based carbonyls mediate pharmacological responses that are achieved through liberation of CO and the nature of the substituents in the organic ligand have a profound effect on both the rate of CO release and cytotoxicity.

Original language	English
Pages (from-to)	403-410
Number of pages	8
Journal	JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume	318
Issue number	1
DOIs	https://doi.org/10.1124/jpet.106.101758
Publication status	Published - Jul 2006

Keywords

PROTEIN-KINASE PATHWAY
HEME OXYGENASE-1
SMOOTH-MUSCLE
CO-RMS
IN-VIVO
CELLS
INHIBITION
INJURY
PROTOPORPHYRIN
STIMULATION

Access to Document

10.1124/jpet.106.101758

Cite this

@article{1ad590e492924feaa0c7b23f09493fbc,

title = "Bioactive properties of iron-containing carbon monoxide-releasing molecules",

abstract = "Carbon monoxide-releasing molecules (CO-RMs) are compounds capable of delivering controlled amounts of CO within a cellular environment. Ruthenium-based carbonyls [tricarbonyldichloro ruthenium(II) dimer and tricarbonylchloro(glycinato) ruthenium(II)] and boronacorbonates (sodium boranocarbonate) have been shown to promote vasodilatory, cardioprotective, and anti-inflammatory activities in a variety of experimental models. Here, we extend our previous studies by showing that eta-4-(4-bromo-6-methyl-2-pyrone) tricarbonyl iron (0) (CORM-F3), an irontricarbonyl complex that contains a 2-pyrone motif, liberates CO in vitro and exerts pharmacological actions that are typical of CO gas. Specifically, CORM-F3 caused vasorelaxation in isolated aortic rings and inhibited the inflammatory response (e.g., nitrite production) of RAW264.7 macrophages stimulated with endotoxin in a dose-dependent fashion. By analyzing the rate of CO release, we found that when the bromide at the 4-position of the 2-pyrone CORM-F3 is substituted with a chloride group [eta-4-(4-chloro-6-methyl-2pyrone) tricarbonyl iron (0) (CORM-F8)], the rate of CO release is significantly decreased (4.5-fold), and a further decrease is observed when the 4- and 6-positions are substituted with a methyl group [eta-4-(4-methyl-6-methyl-2-pyrone) tricarbonyl iron (0) CORM-F11)] or a hydrogen [eta-4-(4-chloro-2-pyrone) tricarbonyl iron (0) CORM-F7)], respectively. Interestingly, the compounds containing halogens at the 4- position and the methyl at the 6-position of the 2-pyrone ring (CORM-F3 and CORM-F8) were found to be less cytotoxic compared with other CO-RMs when tested in RAW246.7 macrophages. Thus, iron-based carbonyls mediate pharmacological responses that are achieved through liberation of CO and the nature of the substituents in the organic ligand have a profound effect on both the rate of CO release and cytotoxicity.",

keywords = "PROTEIN-KINASE PATHWAY, HEME OXYGENASE-1, SMOOTH-MUSCLE, CO-RMS, IN-VIVO, CELLS, INHIBITION, INJURY, PROTOPORPHYRIN, STIMULATION",

author = "P Sawle and J Hammad and Fairlamb, {I J S} and B Moulton and O'Brien, {C T} and Lynam, {J M} and Duhme-Klair, {A K} and R Foresti and R Motterlini",

year = "2006",

month = jul,

doi = "10.1124/jpet.106.101758",

language = "English",

volume = "318",

pages = "403--410",

journal = "JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS",

issn = "0022-3565",

publisher = "American Society for Pharmacology and Experimental Therapeutics",

number = "1",

}

TY - JOUR

T1 - Bioactive properties of iron-containing carbon monoxide-releasing molecules

AU - Sawle, P

AU - Hammad, J

AU - Fairlamb, I J S

AU - Moulton, B

AU - O'Brien, C T

AU - Lynam, J M

AU - Duhme-Klair, A K

AU - Foresti, R

AU - Motterlini, R

PY - 2006/7

Y1 - 2006/7

N2 - Carbon monoxide-releasing molecules (CO-RMs) are compounds capable of delivering controlled amounts of CO within a cellular environment. Ruthenium-based carbonyls [tricarbonyldichloro ruthenium(II) dimer and tricarbonylchloro(glycinato) ruthenium(II)] and boronacorbonates (sodium boranocarbonate) have been shown to promote vasodilatory, cardioprotective, and anti-inflammatory activities in a variety of experimental models. Here, we extend our previous studies by showing that eta-4-(4-bromo-6-methyl-2-pyrone) tricarbonyl iron (0) (CORM-F3), an irontricarbonyl complex that contains a 2-pyrone motif, liberates CO in vitro and exerts pharmacological actions that are typical of CO gas. Specifically, CORM-F3 caused vasorelaxation in isolated aortic rings and inhibited the inflammatory response (e.g., nitrite production) of RAW264.7 macrophages stimulated with endotoxin in a dose-dependent fashion. By analyzing the rate of CO release, we found that when the bromide at the 4-position of the 2-pyrone CORM-F3 is substituted with a chloride group [eta-4-(4-chloro-6-methyl-2pyrone) tricarbonyl iron (0) (CORM-F8)], the rate of CO release is significantly decreased (4.5-fold), and a further decrease is observed when the 4- and 6-positions are substituted with a methyl group [eta-4-(4-methyl-6-methyl-2-pyrone) tricarbonyl iron (0) CORM-F11)] or a hydrogen [eta-4-(4-chloro-2-pyrone) tricarbonyl iron (0) CORM-F7)], respectively. Interestingly, the compounds containing halogens at the 4- position and the methyl at the 6-position of the 2-pyrone ring (CORM-F3 and CORM-F8) were found to be less cytotoxic compared with other CO-RMs when tested in RAW246.7 macrophages. Thus, iron-based carbonyls mediate pharmacological responses that are achieved through liberation of CO and the nature of the substituents in the organic ligand have a profound effect on both the rate of CO release and cytotoxicity.

AB - Carbon monoxide-releasing molecules (CO-RMs) are compounds capable of delivering controlled amounts of CO within a cellular environment. Ruthenium-based carbonyls [tricarbonyldichloro ruthenium(II) dimer and tricarbonylchloro(glycinato) ruthenium(II)] and boronacorbonates (sodium boranocarbonate) have been shown to promote vasodilatory, cardioprotective, and anti-inflammatory activities in a variety of experimental models. Here, we extend our previous studies by showing that eta-4-(4-bromo-6-methyl-2-pyrone) tricarbonyl iron (0) (CORM-F3), an irontricarbonyl complex that contains a 2-pyrone motif, liberates CO in vitro and exerts pharmacological actions that are typical of CO gas. Specifically, CORM-F3 caused vasorelaxation in isolated aortic rings and inhibited the inflammatory response (e.g., nitrite production) of RAW264.7 macrophages stimulated with endotoxin in a dose-dependent fashion. By analyzing the rate of CO release, we found that when the bromide at the 4-position of the 2-pyrone CORM-F3 is substituted with a chloride group [eta-4-(4-chloro-6-methyl-2pyrone) tricarbonyl iron (0) (CORM-F8)], the rate of CO release is significantly decreased (4.5-fold), and a further decrease is observed when the 4- and 6-positions are substituted with a methyl group [eta-4-(4-methyl-6-methyl-2-pyrone) tricarbonyl iron (0) CORM-F11)] or a hydrogen [eta-4-(4-chloro-2-pyrone) tricarbonyl iron (0) CORM-F7)], respectively. Interestingly, the compounds containing halogens at the 4- position and the methyl at the 6-position of the 2-pyrone ring (CORM-F3 and CORM-F8) were found to be less cytotoxic compared with other CO-RMs when tested in RAW246.7 macrophages. Thus, iron-based carbonyls mediate pharmacological responses that are achieved through liberation of CO and the nature of the substituents in the organic ligand have a profound effect on both the rate of CO release and cytotoxicity.

KW - PROTEIN-KINASE PATHWAY

KW - HEME OXYGENASE-1

KW - SMOOTH-MUSCLE

KW - CO-RMS

KW - IN-VIVO

KW - CELLS

KW - INHIBITION

KW - INJURY

KW - PROTOPORPHYRIN

KW - STIMULATION

U2 - 10.1124/jpet.106.101758

DO - 10.1124/jpet.106.101758

M3 - Article

SN - 0022-3565

VL - 318

SP - 403

EP - 410

JO - JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

JF - JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

IS - 1

ER -