Mitochondrial Impairment by Cyanine-Based Small Molecules Induces Apoptosis in Cancer Cells

Mitochondrion, the powerhouse of the cells, has emerged as one of the unorthodox targets in Anticancer therapy due to its involvement in several cellular functions. However, the development of small molecules for selective mitochondrial damage in Cancer cells remained limited and less explored. To address this, in our work, we have synthesized a natural product inspired cyanine-based 3-methoxy pyrrole small molecule library by a concise strategy. This strategy involves Vilsmeier and Pd(0) catalyzed Suzuki cross-coupling reactions as key steps. The screening of the library members in HeLa cervical Cancer cells revealed two new molecules that localized into subcellular mitochondria and damaged them. These small molecules perturbed antiapoptotic (Bcl-2/Bcl-xL) and pro-apoptotic (Bax) proteins to produce Reactive Oxygen Species (ROS). Molecular docking studies showed that both molecules bind more tightly with the BH3 domain of Bcl-2 proteins compared to obatoclax (a pan-Bcl-2 inhibitor). These novel small molecules arrested the cell cycle in the G0/G1 phase, cleaved Caspase-3/9, and finally prompted late Apoptosis. This small molecule-mediated mitochondrial damage induced remarkably high cervical Cancer cell death. These unique small molecules can be further explored as chemical biology tools and next-generation organelle-targeted Anticancer therapy.