TY - JOUR
T1 - Isostructural Re(I)/Tc-99m(I) tricarbonyl complexes for cancer theranostics
AU - Nunes, Patrique
AU - Morais, Goreti Ribeiro
AU - Palma, Elisa
AU - Silva, Francisco
AU - Oliveira, Maria Cristina
AU - Ferreira, Vera F. C.
AU - Mendes, Filipa
AU - Gano, Lurdes
AU - Vicente Miranda, Hugo
AU - Outeiro, Tiago F.
AU - Santos, Isabel
AU - Paulo, Antonio
PY - 2015
Y1 - 2015
N2 - Merging classical organic anticancer drugs with metal-based compounds in one single molecule offers the possibility of exploring new approaches for cancer theranostics, i.e. the combination of diagnostic and therapeutic modalities. For this purpose, we have synthesized and biologically evaluated a series of Re(I)/Tc-99m(I) tricarbonyl complexes (Re1-Re4 and Tc1-Tc4, respectively) stabilized by a cysteamine-based (N,S,O) chelator and containing 2-(4'-aminophenyl) benzothiazole pharmacophores. With the exception of Re1, all the Re complexes have shown a moderate cytotoxicity in MCF7 and PC3 cancer cells (IC50 values in the 15.9-32.1 mu M range after 72 h of incubation). The cytotoxic activity of the Re complexes is well correlated with cellular uptake that was quantified using the isostructural (99)mTc congeners. There is an augmented cytotoxic effect for Re3 and Re4 (versus Re1 and Re2), and the highest cellular uptake for Tc3 and Tc4, which display a long ether-containing linker to couple the pharmacophore to the (N,S,O)-chelator framework. Moreover, fluorescence microscopy clearly confirmed the cytosolic accumulation of the most cytotoxic compound (Re3). Biodistribution studies of Tc1-Tc4 in mice confirmed that these moderately lipophilic complexes (log D-o/w = 1.95-2.32) have a favorable bioavailability. Tc3 and Tc4 presented a faster excretion, as they undergo metabolic transformations, in contrast to complexes Tc1 and Tc2. In summary, our results show that benzothiazole-containing Re(I)/Tc-99m(I) tricarbonyl complexes stabilized by cysteamine-based (N,S,O)-chelators have potential to be further applied in the design of new tools for cancer theranostics.
AB - Merging classical organic anticancer drugs with metal-based compounds in one single molecule offers the possibility of exploring new approaches for cancer theranostics, i.e. the combination of diagnostic and therapeutic modalities. For this purpose, we have synthesized and biologically evaluated a series of Re(I)/Tc-99m(I) tricarbonyl complexes (Re1-Re4 and Tc1-Tc4, respectively) stabilized by a cysteamine-based (N,S,O) chelator and containing 2-(4'-aminophenyl) benzothiazole pharmacophores. With the exception of Re1, all the Re complexes have shown a moderate cytotoxicity in MCF7 and PC3 cancer cells (IC50 values in the 15.9-32.1 mu M range after 72 h of incubation). The cytotoxic activity of the Re complexes is well correlated with cellular uptake that was quantified using the isostructural (99)mTc congeners. There is an augmented cytotoxic effect for Re3 and Re4 (versus Re1 and Re2), and the highest cellular uptake for Tc3 and Tc4, which display a long ether-containing linker to couple the pharmacophore to the (N,S,O)-chelator framework. Moreover, fluorescence microscopy clearly confirmed the cytosolic accumulation of the most cytotoxic compound (Re3). Biodistribution studies of Tc1-Tc4 in mice confirmed that these moderately lipophilic complexes (log D-o/w = 1.95-2.32) have a favorable bioavailability. Tc3 and Tc4 presented a faster excretion, as they undergo metabolic transformations, in contrast to complexes Tc1 and Tc2. In summary, our results show that benzothiazole-containing Re(I)/Tc-99m(I) tricarbonyl complexes stabilized by cysteamine-based (N,S,O)-chelators have potential to be further applied in the design of new tools for cancer theranostics.
KW - BETA-AMYLOID PLAQUES
KW - ALZHEIMERS-DISEASE
KW - ANTITUMOR BENZOTHIAZOLES
KW - BIOLOGICAL EVALUATION
KW - RADIOPHARMACEUTICALS
KW - TC-99M
KW - AGENTS
KW - CHELATORS
KW - POTENT
KW - CELLS
U2 - 10.1039/c5ob00124b
DO - 10.1039/c5ob00124b
M3 - Article
C2 - 25849043
SN - 1477-0520
VL - 13
SP - 5182
EP - 5194
JO - Organic & Biomolecular Chemistry
JF - Organic & Biomolecular Chemistry
IS - 18
ER -