Exploring Dacarbazine Complexation with a Cellobiose-Based Carrier: A Multimethod Theoretical, NMR, and Thermochemical Study

Dacarbazine (DTIC) is a clinically important anticancer drug whose photosensitivity poses challenges for its stability and interactions with supramolecular hosts. Here, we investigate its complexation with the host 1,10-<i>N,N'</i>-bis-(β-D-ureidocellobiosyl)-4,7,13,16-tetraoxa-1,10-diazacyclooctadecane (TN), a hybrid urea-carbohydrate-diazacrown system, using combined experimental and computational approaches. While TN has been studied as a host molecule, its specific interactions with DTIC and the associated thermodynamic characteristics had not been characterized. Computational results (obtained at the density functional theory level (DFT)) indicate that TN primarily forms non-inclusion complexes, with DTIC engaging in hydrogen bonding with sugar units, urea bridges, and diazacrown ether moieties. Experimental ¹H NMR studies in D₂O confirmed these interaction patterns, showing notable chemical shifts for sugar protons. Conductometric measurements between 293 and 313 K allowed for the determination of formation constants and thermodynamic parameters. The results demonstrate that TN:DTIC complexation is spontaneous, exothermic, and enthalpy-driven, accompanied by decreased system entropy. Comparison with previous studies on cyclodextrin complexes shows that TN forms strong associations with DTIC, owing to its abundant donor-acceptor groups, which facilitate extensive hydrogen-bonding networks. These findings provide new insights into DTIC stabilization and highlight TN's potential as a multifunctional platform for drug delivery.