From Tunable Chalcogen Bonding to Enhanced Chemotherapeutic Properties

Organochalcogen species have recently emerged as potential alternative candidates for chemotherapeutic drug design. From a molecular recognition perspective, the chalcogen atoms in these compounds offer variable σ-hole potentials through electron-withdrawing groups, sp-hybridization, and atom-to-atom substitution. This adaptability does, in turn, provide some control over the way in which the selectivity and binding strength of small molecules capable of chalcogen bonding (ChB) can be fine-tuned in a biological system. In this context, a total of eight molecules were synthesized 4Cl-Ch, 4CN-Ch, 4NO₂-Ch, and 35DN-Ch (Ch = Se/Te), and their single crystal structures were examined. Electronic structure calculations show that the electrostatic potential at the two σ-holes on the chalcogen atom can be tuned by substituting selenium with tellurium, by modifying the electron-withdrawing capacity of the phenyl group substituents from 4Cl to 35DN and by varying the orientation of the phenyl groups. The two σ-holes show different degrees of sensitivity to these parameters, allowing for further tunability of these bidirectional σ-hole interactions. Biological evaluations showed a strong correlation between σ-hole activation and anticancer activity, with tellurium compound 35DN-Te demonstrating potent activity against HeLa cells (IC₅₀ = 2.9 μM), outperforming traditional drugs like cis-platin. These findings highlight ChB’s potential for developing novel chemotherapeutics.