First organometallic inhibitors for human thymidine kinase: synthesis and in vitro evaluation of rhenium(I)- and technetium(I)-tricarbonyl complexes of thymidine

Six 5′-carboxamide derivatives of 5′-aminothymidine have been synthesized with alkyl chains of various length and a tridentate, imino diacetic acid based chelating system. The thymidine analogues have been reacted with the precursor fac-[M(H2O)3(CO)3]+ (M=99mTc, Re) in aqueous media to form, water-soluble and stable organometallic complexes in good yields. 1H-NMR and IR spectroscopic analyses confirmed in all cases the tridentate complexation of the metal-tricarbonyl fragment exclusively via the tridentate chelates, and no unspecific interaction with other functional groups of the pharmacophor. The organometallic rhenium–nucleoside complexes have been tested in vitro for competitive inhibition of human cytosolic thymidine kinase (hTK1) and herpes simplex virus thymidine kinase type 1 (HSV1-TK). In case of hTK1 it could be observed, that the inhibition capacity of the complexes improved with increasing spacer length. On the other hand, all six complexes showed no or only slight inhibition of the HSV1-TK. The corresponding radioactive technetium-99m complexes have been prepared and challenged for stability in physiological phosphate buffer and human serum albumin at 37 °C for 24 h. Only minor decomposition of the complexes could be detected under these conditions proving the high kinetic inertness and/or stability of these complexes.