Synthesis, reactivity and cytotoxic properties of water soluble coinage metal N-Heterocyclic Carbene complexes

Even if the chemistry of carbenes was discovered fifty years ago, it is only recently that N-heterocyclic carbenes (NHCs)1 have fascinated the researchers showing them to be suitable candidates for medicinal chemistry applications due to both the versatility to bond a lot of transition metals and the ease to fine tuning their structure, influencing both their stability and solubility. NHC complexes of coinage metals have been widely investigated for their variable applications and diverse structural properties and recently they showed to be good candidates as an alternative to cisplatin, exhibiting encouraging results in the field of anticancer drugs research2,3. In the last years, we have developed several classes of coinage metal-NHC complexes obtained from the precursors {[HB(RImH)3]Br2} (R = Bz, Mes and t-Bu), {[H2B(BzTzH)2]Br}, {H2C(HTzR)2} and {H2C(HImR)2} (R = (CH2)3SO3- or (CH2)2COO-).2 Recently we have focused the research work on 11th group metal-NHCs complexes obtained from water soluble 1,3-symmetrically and 1,3-unsymmetrically substituted NHCs precursors based on imidazole and benzoimidazole scaffolds4-6. More recently we have synthesized and investigated the cytotoxic activity of the novel NHC ligand precursor [HTz(pNO2Bz)2]Br, and the corresponding metal complexes M[Tz(pNO2Bz)2]Br (M = Cu(I), Ag(I) or Au(I))7. In addition, novel water soluble bis(NHCSO3)CuCl complexes (NHCSO3 = HImBn,PrSO3, Na(4-Me)ImPrSO3 and NaBzimPrSO3), derived by the sulfonated N-heterocyclic carbene precursors HImBn,PrSO3 (3-(1-benzyl-1H-imidazol-3-ium-3-yl)propane-1-sulfonate), Na(4-Me)HImPrSO3 (sodium 3,3'-(4-methyl-1H-imidazole-3-ium-1,3-diyl)dipropane-1-sulfonate) and NaHBzimPrSO3 (sodium 3,3'-(1H-benzo[d]imidazole-3-ium-1,3-diyl)dipropane-1-sulfonate), have been synthesized8. The in vitro antitumor effects of the complexes and the corresponding free ligands were evaluated on a panel of various human tumour cell lines. Their cytotoxic properties were also evaluated against non-transformed human cells and on a cellular model of cisplatin-resistance.