Chemotherapeutic molecular switch behavior of aryl-substituted tetracarboxylic dianhydrides

In this study, we synthesized aryl-substituted tetracarboxylic acid dianhydride (TCDA) diastereomers having potential for chemoselective DNA alkylation. The TCDAs were obtained through a radical-initiated addition chain reaction. Diastereomeric reaction mixture was characterized by FTIR, UV, EI-MS, and elemental analysis. Quantum Mechanical (QM) calculations, including relaxed potential energy surface (PES) scans at B3LYP/6311+G (d,p) and MP2/6-31G optimizations of global minima of each diastereomer, revealed that the most stable and polar aryl-substituted TCDA diastereomers adopt non-anti dihedral geometries between the two anhydride rings. This conformation effectively reduces nucleophilic accessibility on the C=O, thereby limiting nucleophilic attack under physiological conditions, with possible activation under mildly acidic microenvironments of tumors. The stability and polarity are additional helpful drug attributes. Further validation of reduced reactivity came from biological screening of the aryl-substituted diastereomeric mixture against human HeLa cancer cell line, which demonstrated reduced reactivity compared to alkyl TCDA control analogs, despite both sharing the same crosslinking TCDA arm. These computational and bioactivity results suggest that aryl substitution imposes conformational constraints that induce environment-dependent differences in reactivity. Overall, this study shows that stereoelectronic factors can modulate reactivity, offering a rationale for the development of selective therapeutic agents. Further investigations are underway to evaluate the individual bioactivities of isolated diastereomers.