Facile Synthesis of Hemin Derivatives with Modulated Aggregation Behaviour and Enhanced Nitric-Oxide Scavenging Properties as New Therapeutics for Breast Cancer

Abstract

Nitric oxide (•NO) plays various pathophysiological roles in breast cancer, significantly influencing the migration of tumour cells through concentration gradients. Therefore, modulating •NO levels via selective scavenging presents a promising approach to treating aggressive •NO-dependent cancers, such as triple-negative breast cancer (TNBC). Hemin emerges as a potential scavenger of •NO; however, its metalloporphyrin molecules tend to aggregate in physiological solutions, which limits its biomedical applications. To address this, a modification strategy is employed to minimize aggregation and protect against physiological oxidative degradation while preserving •NO-scavenging properties. This is achieved through a simple chemical transformation that involves hemin conjugation to aromatic residues, tyrosine, and tyramine via carbodiimide reactions. These derivatives exhibit altered electronic properties and oxidation potential compared to hemin, alongside reduced aggregation tendencies and retained •NO-binding affinity in aqueous solutions. Furthermore, depending on the type of hemin derivative, there is an associated inhibition of TNBC cell migration. These model hemin compounds demonstrate varying •NO-binding affinities and resistance levels to oxidative degradation and aggregation, offering insights into the design of •NO-scavenging molecules with enhanced properties for cancer treatment.