-small cell lung cancer. A relatively new alternative to targeting DNA and enzymes in rapidly proliferating cells, or specific signaling pathways is to focus on organelles like the mitochondria. PD-1/PD-L1 inhibitor 2 chemical information mitochondria are the energy generators that maintain cell life and essential cell functions, including multiple signaling cascades that regulate cells, for instance, metabolism, cell cycle control, development, and cell death. In cancer chemotherapy, mitochondria-targeting drugs interfere with cancer cell metabolisms by pertubing the mitochondrial transmembrane potential, inhibiting the electron redox chain complexes, interfering the mitochondria transmembrane permeability, and targeting mitochondrial-DNA. The most common types of mitochondria-targeting drugs are lipophilic, cationic drugs; these are selective for cancer cells because they tend to have higher mitochondrial membrane 19774075 potentials than normal epithelial cells. We have previously reported structure-activity relationships for the anticancer properties of a series of rosamines . These compounds are delocalized lipophilic cations with peripheral cyclic amines and various groups at the meso position; the majority of these cations are substantially more potent than rhodamine-123 which is a well-studied delocalized lipophilic cation. Consistence with this, SAR data for the rosamines suggested good potencies correlated with hydrophobic cyclic amines and meso-aryl substituents. Thiofuryl and 4iodophenyl meso substitution corresponded to approximately 5-fold improvement in potency compared to phenyl substitution. Additionally, the data indicated that significantly lower IC50 values were obtained for unsymmetrical compounds, but the combination of unsymmetrical amine substituents with thiofuryl and 4-iodophenyl meso substitution was not explored. Intracellular imaging on representative examples indicated these Oxidative Phosphorylation Targeting Rosamines compounds accumulate in 
the mitochondria. These compounds are also found to be more cytotoxic against cancer cells compared with immortalized normal epithelial cells of the same organ type. The research reported here was undertaken to probe how two molecular modifications affect cytotoxicities in this series: replacement of para-iodo or thiofuran groups with other parahalide or furan groups; and, combination of thiofuryl and 4iodophenyl meso substitution with piperidine/morpholine combinations. Thus we report syntheses of second generation rosamines and their cytotoxicities relative to a panel of solid tumor cell lines. Compounds with promising activity were further evaluated in the NCI-60 human tumor cell lines screen. Selected rosamines were also examined for their effect on cellular redox systems and for effects in an in vivo tumor model. Materials and Methods Ethics Statement All animal experiments were conducted in accordance with protocols reviewed and approved by Dr. Haji Azizuddin Bin Haji Kamaruddin, Laboratory Animal Centre Animal Care and Use Committee of Faculty of Medicine, University of Malaya. Female BALB/c mice aged between 68 weeks with a minimum weight of 17 g were maintained in a controlled environment of 12 h light-dark cycles with free access to food and purified water. Female mice were used because the hormonal environment essential 3986806 for development of implanted 4TI mouse mammary carcinoma would be present. Materials Minimum essential medium with Earl’s salt and L-glutamine, RPMI 1640 medium with L-glutamine, fetal bovine
