Novel Tricarbonylrhenium-Anthrapyrazole Complexes with DNA-Binding and Antitumor Properties: In Vitro and In Vivo Pharmacokinetic Studies with 99mTc-Analogue

Organometallic complexes of fac-tricarbonylrhenium have been shown to exhibit anticancer properties. Anthrapyrazole anticancer agents act as DNA intercalators and topoisomerase IIα inhibitors, leading to double-strand breaks (DBS) and cell cycle arrest. This work involves the synthesis and biological evaluation of novel fac-tricarbonyl-rhenium complexes with anthrapyrazole derivatives. The anthrapyrazole moiety was synthesized from 1,8-dihydroxyanthraquinone, and three ligands L1, L2 and L3 were prepared. Ligand L1 coordinates via the phenolic O and pyrazole N as bidentate chelator forming the fac-Re(CO)3(κ2-N,O)(MeOH)-type complex, ReL1. Ligand L2 contains a pendant picolylamine N,N′-chelating system, forming the bidentate fac-Re(CO)3(κ2-N,N′)Br-type complex, ReL2. Ligand L3 contains a pendant picolylaminomonoacetic acid chelating system, forming a tridentate fac-Re(CO)3(κ3-N,N′,O)-type complex, ReL3. Complex ReL4 contains a picolylamine chelator, forming a complex with structure fac-Re(CO)3(κ2-N,N′)Br, which was synthesized as a model for ReL2, and its coordination mode was resolved by X-ray crystallography. The complexes were characterized spectroscopically, and their biological properties were evaluated in vitro, in terms of DNA binding as well as for the cytotoxicity against CT-26 tumor cell line. Tumor cell cytotoxicity was high for ligand L2 and complex ReL2, exhibiting IC50 values of 0.36 and 0.64 μΜ, respectively. The most promising complex ReL2 was evaluated further by the preparation of its congener γ-emitting technetium-99m radio-complex, 99mTcL2. The in vitro uptake in CT26 tumor cells and the in vivo uptake in CT26 tumor-bearing mice of 99mTcL2 was determined, and its pharmacokinetic profile was established. These data indicate that the 99mTc complex has suitable properties to enter tumor cells in vitro and in vivo, and therefore ReL2 is promising for further evaluation.