An organometallic inhibitor for the human repair enzyme 7,8-dihydro-8-oxoguanosine triphosphatase.

The probe-based discovery of the first small-molecule inhibitor of the repair enzyme 8-oxo-dGTPase (MTH1) is presented, which is an unconventional cyclometalated ruthenium half-sandwich complex. The organometallic inhibitor with low-nanomolar activity displays astonishing specificity, as verified in tests with an extended panel of protein kinases and other ATP binding proteins. The binding of the organometallic inhibitor to MTH1 is investigated by protein crystallography.

Metal and ligand substitution of the aluminium tris-pyridyl ligands [RAl(2-py')(3)](-) (R = Et, (n)Bu, (s)Bu, (t)Bu; 2-py' = 2-pyridyl, 3-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl).

A series of tris-pyridyl complexes [RAl(2-py)(3)]Li.thf [2-py = 2-pyridyl; R = Et (1); (n)Bu (2); (s)Bu (3), (t)Bu (4)] were prepared by the sequential reaction of AlCl(3) with RLi then 2-Li-py in thf. The related complexes [MeAl{2-(3-Me)py}(3)]Li(mu-Br)Li(thf)(3) (5), [MeAl{2-(5-Me)py}(3)]Li.thf (6) and [MeAl{2-(6-Me)py}(3)]Li.thf (7) are obtained similarly from MeAlCl(2) and the appropriate lithio-pyridine (2-Li-py'). The synthetic approaches used provide the means for extensive elaboration of the [RAl(2-py')(3)](-) ligand frameworks, and potentially broad access to a large range of new anionic tris-pyridyl ligands of this type. Fundamental insights into how the ligand bites and coordination environments offered are modified by substituents at the Al bridgehead and pyridyl rings are given by the solid-state structures of 1-7 .