Ruthenium organometallic fragments for augmenting binding of validated medicinal compounds.
Currently, one of the most promising metals used in the synthesis of anti-tumour compounds for chemotherapeutic application is ruthenium.1 The properties of the metal lend themselves well to medicinal applications in terms of geometry, accessible oxidation states and relevant substitution kinetics and the diversity of ruthenium compounds that show cytotoxicity is somewhat startling (Figure 1).
Fig. 1 - Chemical structures of a selection of ruthenium compounds that display cytotoxicity. Clockwise from top left: NAMI-A1, RAPTA-B3,4, a tri- ruthenium cluster5 and α-[Ru(azpy) 2Cl2]3.6
The targets of ruthenium-based antitumour compounds have yet to be defined, however, and so the rationale design of new, more potent compounds presents a problem. Recently, a small body of research has been aimed at the "directing" of precious metal interactions to specific enzymatic targets by connection of such complexes to an organic ligand. Precious metals are ideally suited to this end; their (relatively slow) ligand exchange rates are similar to the lifetimes of cellular processes and they are capable of forming highly energetically-favourable coordination bonds to the physiological target. Owing to their enthalpic favourability, as few as one or two such bonds would be sufficient to impart a marked increase on target inhibition. Indeed, given the hypothesis of Kuntz et al7, it is predicted that compounds of this nature should display augmented ligand efficiency compared with the organic directing molecule alone.
The aim of my research is to build ruthenium organometallic groups into validated, medicinal compounds such that the ligand efficiency of these existing compounds can be improved upon. In the longer term, it is hoped that the central approach described will set a precedent for inclusion of metal-containing fragments in libraries for fragment assembly. The capacity to dramatically increase ligand efficiency and to offer tunable lability and variable hypervalancy within a library could signal a new era in the field of fragment-based drug discovery and medicinal pharmaceuticals.
1 Page S, Boss S and Barker P: Tuning heavy metal compounds for anti-tumor activity: is diversity the key to ruthenium's success? Future Med. Chem., 1,(3), 541-559, (2009))
2 Rademaker-Lakhai, JM, D van den Bongard, D Pluim, JH Beijnen, JHM Schellens: A phase I and pharmacological study with imidazolium-trans-DMSO-imidazole- tetrachlororuthenate, a novel ruthenium anticancer agent. Clinical Cancer Research 10, 3717-3727 (2004)
3 Allardyce, CS, PJ Dyson, DJ Ellis, SL Heath: [Ru(eta(6)-p-cymene)Cl-2(pta)] (pta=1,3,5-triaza-7-phosphatricyclo[18.104.22.168]decane): a water soluble compound that exhibits pH dependent DNA binding providing selectivity for diseased cells. Chemical Communications 1396-1397 (2001).
4 Scolaro, C, A Bergamo, L Brescacin et al.: In vitro and in vivo evaluation of ruthenium(II)-arene PTA complexes. Journal of Medicinal Chemistry 48, 4161-4171 (2005).
5 Therrien, B, WH Ang, F Cherioux et al.: Remarkable anticancer activity of triruthenium-arene clusters compared to tetraruthenium-arene clusters. Journal of Cluster Science 18, 741-752 (2007)
6 Velders, AH, H Kooijman, AL Spek, JG Haasnoot, D de Vos, J Reedijk: Strong differences in the in vitro cytotoxicity of three isomeric dichlorobis(2- phenylazopyridine)ruthenium(II) complexes. Inorganic Chemistry39, 2966-+ (2000)
7 Kuntz, D., Chen, K., Sharp, K.A., Kollman, P.A.: The maximal affinity of ligands, PNAS, 96, 9997-10002, (1999)