Modified peroxamide-based reactive oxygen species (ROS)-responsive doxorubicin prodrugs.

Reactive oxygen species (ROS) plays a pivotal physiological role in intracellular signaling of any living organism. Due to the elevated levels of ROS in tumor microenvironment than normal tissues, an increasing number of ROS-responsive probes and prodrugs is being studied for the fight against cancer. This study describes the design and synthesis of a panel of novel modified peroxamide-based ROS-responsive prodrugs of doxorubicin, among which the OH-mOX-Dox prodrug showed very stable and highly specific ROS sensitivity. This novel Dox prodrug exerted potent anti-proliferation effects against the two breast cancer cell lines of MDA-MB-468 and MDA-MB-231 while it showed minimal toxicity toward the normal breast cell line, MCF-12A. The cytotoxicity of the OH-mOX-Dox prodrug was significantly enhanced at elevated ROS levels after co-incubation with l-buthionine sulfoximine (BSO). Our clonogenic assay data validated that enhanced intracellular ROS level upon X-ray irradiation resulted in an increase in the efficacy of the OH-mOX-Dox prodrug against the two breast cancer cell lines.

IODVA1, a guanidinobenzimidazole derivative, targets Rac activity and Ras-driven cancer models.

We report the synthesis and preliminary characterization of IODVA1, a potent small molecule that is active in xenograft mouse models of Ras-driven lung and breast cancers. In an effort to inhibit oncogenic Ras signaling, we combined in silico screening with inhibition of proliferation and colony formation of Ras-driven cells. NSC124205 fulfilled all criteria. HPLC analysis revealed that NSC124205 was a mixture of at least three compounds, from which IODVA1 was determined to be the active component. IODVA1 decreased 2D and 3D cell proliferation, cell spreading and ruffle and lamellipodia formation through downregulation of Rac activity. IODVA1 significantly impaired xenograft tumor growth of Ras-driven cancer cells with no observable toxicity. Immuno-histochemistry analysis of tumor sections suggests that cell death occurs by increased apoptosis. Our data suggest that IODVA1 targets Rac signaling to induce death of Ras-transformed cells. Therefore, IODVA1 holds promise as an anti-tumor therapeutic agent.

UV cell stress induces oxidative cyclization of a protective reagent for DNA damage reduction in skin explants.

UV irradiation is a major driver of DNA damage and ultimately skin cancer. UV exposure leads to persistent radicals that generate ROS over prolonged periods of time. Toward the goal of developing long-lasting antioxidants that can penetrate skin, we have designed a ROS-initiated protective (RIP) reagent that, upon reaction with ROS (antioxidant activity), self-cyclizes and then releases the natural product apocynin. Apocynin is a known antioxidant and inhibitor of NOX oxidase enzymes. A key phenol on the compound 1 controls ROS-initiated cyclization and makes 1 responsive to ROS with a EC50 comparable to common antioxidants in an ABTS assay. In an in vitro DNA nicking assay, the RIP reagent prevented DNA strand breaks. In cell-based assays, the reagent was not cytotoxic, apocynin was released only in cells treated with UVR, reduced UVR-induced cell death, and lowered DNA lesion formation. Finally, topical treatment of human skin explants with the RIP reagent reduced UV-induced DNA damage as monitored by quantification of cyclobutane dimer formation and DNA repair signaling via TP53. The reagent was more effective than administration of a catalase antioxidant on skin explants. This chemistry platform will expand the types of ROS-activated motifs and enable inhibitor release for potential use as a long-acting sunscreen.