Dalton Transactions Dynamic Article Links Cite this: DOI: 10.1039/c1dt10125k www.rsc.org/dalton PAPER [Mn(CO) 4 {S 2 CNMe(CH 2 CO 2 H)}], a new water-soluble CO-releasing molecule† Sian H. Crook, a Brian E. Mann, a Anthony J. H. M. Meijer, a Harry Adams, a Philip Sawle, b David Scapens a and Roberto Motterlini c Received 21st January 2011, Accepted 2nd February 2011 DOI: 10.1039/c1dt10125k [Mn(CO) 4 {S 2 CNMe(CH 2 CO 2 H)}], 1, is shown to be a CO releasing molecule providing at least three moles CO per mole of compound. The mechanism of CO loss is dissociative and reversible and was investigated using Gaussian 09 calculations. The reversible binding of CO results in a relatively stable solution of the compound, while in the presence of a CO receptor or a ligand to prevent the rebinding of CO, the CO is lost rapidly. The X-ray structure was determined. Introduction Like NO and H 2 S, CO is an important signalling molecule in mammals, especially in the cardiovascular system. 1–3 The administration of CO in animals has been shown to have a wide range of physiological effects 4 and is particularly beneficial in the cardiovascular system 5–7 and inflammation. 8 As a consequence, there is considerable interest in its medical applications 9,10 and there are clinical trials on its use to prevent lung inflammation, 11 in kidney transplant patients, 12 and to treat patients with intestinal paralysis after colon surgery. 13 We have been developing the use of metal carbonyls as pro- drugs to release CO in vivo as the administration of CO in solution or solid provides a way to administer CO in a controlled local dose rather than inhaled gas to the whole patient. A number of compounds was published in the initial patent, 14 and subsequently a selection appeared in papers. The initial paper reported the use of [Mn 2 (CO) 10 ], [Ru(CO) 3 Cl 2 ] 2 and [Fe(CO) 5 ] as CO-releasing molecules, CO-RMs. 15 It was shown that [Mn 2 (CO) 10 ], on ir- radiation, and [Ru(CO) 3 Cl 2 ] 2 produce vasodilatation, attenuate coronary vasoconstriction and reduces acute hypertension. 15 As neither [Mn 2 (CO) 10 ] and [Ru(CO) 3 Cl 2 ] 2 are water soluble, a water soluble version of [Ru(CO) 3 Cl 2 ] 2 ,[fac-Ru(CO) 3 Cl(glycinate)], was developed. 16 These initial discoveries have been taken up by other researchers and there are now over 200 papers describing the a Department of Chemistry, University of Sheffield, Sheffield, United King- dom S3 7HF. E-mail: b.mann@sheffield.ac.uk; Fax: 0044 (0)114 2738673; Tel: 0044 (0)114 2229332 b Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, United Kingdom c Department of Drug Discovery and Development, Italian Institute of Technology, Via Morego, 30, 16163, Genova, ITALY. E-mail: roberto. motterlini@iit.it; Fax: +39-01072032; Tel: +39-01071781547 † Electronic supplementary information (ESI) available: Full experimental details and data, and calculated structures. CCDC reference number 787948. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1dt10125k use of CO-RMs and the development of new CO-RMs. 3 Many studies have involved the use of [fac-Ru(CO) 3 Cl(glycinate)] which appears to be excellent from the biological viewpoint. However it has an extensive solution chemistry that makes purification difficult. 17 As a consequence there is considerable interest in developing new CO-RMs. There are now examples based on V, Cr, Mo, W, Mn, Re, Fe, Ru, Co and B, see a recent review. 3 Of particular relevance to this paper are [Mn(CO) 5 X], X = Cl, Br, I, which are biologically active albeit releasing CO very slowly, 18 and a number of derivatives of [{E(pz) 3 }Mn(CO) 3 ] + ,E = RC or P, which release CO on photolysis. 19–22 Of particular medical relevance, [Mn(CO) 5 Br] strongly reduces the viability of E. coli and S. aureus, 23 and [{HC(pz) 3 }Mn(CO) 3 ]PF 6 has a significant photoinduced cytotoxicity to HT29 colon cancer cells, comparable to that of established agent 5-fluorouracil. 19 Results and discussion Synthesis, characterisation and X-ray structure Recently we have discovered a new class of CO-RMs based on [Mn(CO) 4 (S 2 CNR 2 )] and reported them in a patent. 24 In this pub- lication the introduction of a water solubilising group, -CH 2 CO 2 H in [Mn(CO) 4 (S 2 CNMeCH 2 CO 2 H)] (1) is described. The presence of the –CH 2 CO 2 H group makes the compound ideal for biological use being soluble in organic solvents when protonated for synthesis and soluble in water when deprotonated at physiological pH 7.4. The ligand, Na[S 2 CN(CH 3 )CH 2 COONa] is synthesised according to the literature. 25 1 is easily made from [Mn(CO) 5 Br] and Na[S 2 CN(CH 3 )CH 2 COONa] based on the published synthesis of [Mn(CO) 4 (S 2 NEt 2 )] 26 and purified by acidification of an aqueous solution of the initial product, [Mn(CO) 4 (S 2 CNMeCH 2 CO 2 H)] in water to precipitate 1. 1 was characterised by IR (CO stretches) and 1 H and 13 C NMR spectroscopy, mass spectrometry and elemental analysis, see experimental. The structure was confirmed by X-ray crystallography, see Fig. 1. This journal is © The Royal Society of Chemistry 2011 Dalton Trans. Downloaded by Imperial College London on 15 March 2011 Published on 14 March 2011 on http://pubs.rsc.org | doi:10.1039/C1DT10125K View Online