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

Abstract

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.

Multifunction in One Molecule: Mitochondrial Imaging and Photothermal & Photodynamic Cytotoxicity of Fast-Response Near-Infrared Fluorescent Probes with Aggregation-Induced Emission Characteristics

“…Apoptosis is the autonomous and orderly death of cells controlled by genes and plays a vital role in maintaining the stability of the internal environment. Uncontrolled apoptosis may lead to degenerative diseases, cancer, autoimmunity, etc . since the apoptotic pathway is generally inhibited in cancer cells.…”

“…Uncontrolled apoptosis may lead to degenerative diseases, cancer, autoimmunity, etc. 33 since the apoptotic pathway is generally inhibited in cancer cells. Therefore, apoptosis is a good target in anticancer treatments and many drugs show anticancer activity by activating the apoptotic pathway.…”

Small molecule induces mitochondrial impairment in colon cancer cells

“…[25][26][27][28] However, the effect of 3methoxy-pyrrole on mitochondrial impairment towards anticancer therapy is elusive and less explored. [29][30][31][32][33][34] To address this, in this manuscript we have developed a concise strategy to synthesize a small library of 3-methoxypyrrole derivatives using modified Vilsmeier reaction and Suzuki coupling reaction as the key steps. One of the library members was identified to localize into the mitochondria of HCT-116 colorectal cancer cells within 3 h leading to mitochondrial morphology damage by inhibiting anti-apoptotic Bcl-2, followed by generation of reactive oxygen species (ROS).…”

“…25–28 However, the effect of 3-methoxy-pyrrole on mitochondrial impairment towards anti-cancer therapy is elusive and less explored. 29–34…”

Mitochondria Targeted AIE Probes for Cancer Phototherapy

“…However, these chemotherapeutic drugs have low specificity toward the cancer cells, rendering drug resistance and inducing side effects as collateral damage. , To overcome these challenges, the development of novel small molecules for impairing unorthodox targets in cancer cells evolved as an alternative strategy. In this context, the mitochondrion has gained the spotlight of the scientific community as one of the most interesting targets for anticancer therapeutics due to its key role in myriads of biological phenomena including bioenergetics, biosynthesis, stress response, signaling, and metabolism as well as maintaining the mitochondrial genomic integrities, which are dysregulated in cancer generation, development, and progression. − As a result, small molecule probes for imaging and impairing mitochondria emerged as an alternative strategy to target cancer. − In this light, aggregation-induced emission probes (AIEgens) showed immense potential in recent years.…”