DZ-1 (Central South University)

Artesunate (ART), a well-established antimalarial agent, has demonstrated promising anticancer activity in both in vitro and in vivo studies. Despite its potential, clinical application of ART in oncology is limited by modest efficacy and dose-limiting toxicity, likely due to nonspecific accumulation in normal tissues. Targeted delivery strategies are therefore essential to enhance therapeutic selectivity and reduce off-target effects. To this end, ART has been conjugated with targeting molecules such as aptamers, dyes, and polymers. DZ-1, a heptamethine cyanine dye, selectively accumulates in cancer cells through overexpression of organic anion transporting polypeptides (OATPs), offering a promising vehicle for tumor-specific delivery. In this study, we evaluated the anticancer efficacy and underlying mechanisms of a novel conjugate of DZ-1 and ART (DZ-1-ART) in three human cancer cell lines: colon cancer (HCT116), pancreatic cancer (BxPC-3), and breast cancer (MCF-7). DZ-1-ART induced time-dependent cytotoxicity across all tested cancer cell lines. Mechanistically, DZ-1-ART localized to both mitochondria and lysosomes, but functional studies indicated that lysosomes were not essential for its pro- apoptotic activity. Instead, DZ-1-ART triggered mitochondria-mediated apoptosis via a Bid-, Bax-, and Bak-independent pathway, leading to caspase-3 activation and cell death. Our findings demonstrate that DZ-1-ART undergoes intracellular trafficking through lysosomes and mitochondria, but induces apoptosis primarily through a mitochondrial, Bid-Bax/Bak- independent, caspase-3-dependent pathway. These results support the development of DZ-1- ART as a tumor-targeted anticancer agent with potential applications in theranostics.

Overexpression of the efflux pump is a predominant mechanism by which bacteria show antimicrobial resistance (AMR) and leads to the global emergence of multidrug resistance (MDR). In this work, the inhibitory potential of library of dihydronapthyl scaffold-based imidazole derivatives having structural resemblances with some known efflux pump inhibitors (EPI) were designed, synthesized and evaluated against efflux pump inhibitor against overexpressing bacterial strains to study the synergistic effect of compounds and antibiotics. Out of 15 compounds, four compounds (Dz-1, Dz-3, Dz-7, and Dz-8) were found to be highly active. DZ-3 modulated the MIC of ciprofloxacin, erythromycin, and tetracycline by 128-fold each against 1199B, XU212 and RN4220 strains of S. aureus respectively. DZ-3 also potentiated tetracycline by 64-fold in E. coli AG100 strain. DZ-7 modulated the MIC of both tetracycline and erythromycin 128-fold each in S. aureus XU212 and S. aureus RN4220 strains. DZ-1 and DZ-8 showed the moderate reduction in MIC of tetracycline in E. coli AG100 only by 16-fold and 8-fold, respectively. DZ-3 was found to be the potential inhibitor of NorA as determined by ethidium bromide efflux inhibition and accumulation studies employing NorA overexpressing strain SA-1199B. DZ-3 displayed EPI activity at non-cytotoxic concentration to human cells and did not possess any antibacterial activity. Furthermore, molecular docking studies of DZ-3 was carried out in order to understand the possible binding sites of DZ-3 with the active site of the protein. These studies indicate that dihydronaphthalene scaffolds could serve as valuable cores for the development of promising EPIs.