Rhenium tricarbonyl complexes as potential anticancer agents: a versatile approach for novel drug discovery and development

Abstract

Diethylenetriamine can serve as a bidentate as well as a tridentate ligand in coordination chemistry. Here we have synthesized asymmetric tridentate N donor ligands derived from diethylenetriamine with the aromatic groups; chlorobenzene and iodobenzene linked to a terminal nitrogen through a sulfonamide linkage. Two novel sulfonamide ligands; N(SO2chlorobenzene) dienH (L1) and N(SO2iodobenzene)dienH (L2) and their net neutral Re(I) tricarbonyl complexes; [Re(CO)3(N(SO2chlorobenzene)dien)] (C1) and [Re(CO)3(N(SO2iodobenzene)dien)] (C2) were synthesized. They were characterized using spectroscopic methods including 1H NMR, fluorescence, UV-Visible and FT-IR. ‘SwissTargetPrediction’ and ‘SwissADME’ servers were used for biological target predictions. Molegro Virtual Docker 2013.6.0.1 software was used to conduct the molecular docking study. Furthermore, BSA binding experiment was performed with UV-visible spectroscopic titrations. In UV-visible spectra, high energy absorption bands between 200 nm – 300 nm indicate the intraligand ᴫ-ᴫ* and n-ᴫ* transitions. High fluorescence intensities were observed for the ligands in the visible range while quenched fluorescence intensities were observed for their corresponding Re complexes. This lowered fluorescence may be due to the quenching of fluorescence upon coordinating of the ligand with the metal ion. The S-N stretching vibration appeared in free ligands; L1 and L2 have shifted towards higher frequencies in corresponding Re complexes; C1 and C2. 1H NMR spectra recorded in DMSO-d6 confirm that, upon complexation with the metal Re, the sulfonamide nitrogen deprotonates and two protons of the terminal nitrogen of the complexes orient toward (endo-NH) and away (exo-NH) from the CO ligands. The two ligands fulfill the requirements of Lipinski’s rule of 5 and exhibit an excellent bioavailability score of 0.55. Moreover, both ligands are predicted to bind with sigma receptors, an important drug target in the development of anticancer agents. L1, L2 and C1 showed MolDock scores of -94.83, -91.93 and -121.21, respectively for sigma receptors. In the BSA binding study, the calculated binding constant, Kb values for L1, L2, C1 and C2 are 7.44 x 104 M-1, 22.79 x 104 M-1, 54.27 x 104 M-1 and 2.62 x 104 M-1, respectively and are within the accepted range of Kb for drug-carrier complexes. The promising outcomes of in silico analysis and BSA binding study of these sulfonamide ligands and Re(I) complexes reveal that these compounds have the potential to be developed as anticancer drug leads and serum albumin could act as a good carrier to transport these compounds in vivo.