Boosting Type‑I and Type-II ROS Production of Water-Soluble Porphyrin for Efficient Hypoxic Tumor Therapy

As the most successful clinically approved photosensitizers, porphyrins have been extensively employed in the photodynamic therapy (PDT) of cancers. However, their poor water solubility, aggregation-induced self-quenching on ROS generation, and a low tolerance for a hypoxic condition usually result in unsatisfied therapeutic outcomes. Therefore, great efforts have been dedicated to improving the PDT efficacy of porphyrin-type photosensitizers in treating hypoxic tumors, including combination with additional active components or therapies, which can significantly complicate the therapeutic process. Herein, we report a novel water-soluble porphyrin with O-linked cationic side chains, which exhibits good water solubility, high photostability, and significantly enhanced ROS generation efficacy in both type-I and type-II photodynamic pathways. We have also found that the end charges of side chains can dramatically affect the ROS generation of the porphyrin. The cationic porphyrin exhibited high in vitro PDT efficacy with low IC50 values both in normoxia and hypoxia. Hence, during in vivo PDT study, the cationic porphyrin displayed highly effective tumor ablation capability. This study demonstrates the power of side-chain chemistry in tuning the photodynamic property of porphyrin, which offers a new effective strategy to enhance the anticancer performance of photosensitizers for fulfilling the increasing demands for cancer therapy in clinics

Rhodamine-Functionalized Graphene Quantum Dots for Detection of Fe³⁺ in Cancer Stem Cells

A turn-on orange-red fluorescent nanosensor based on rhodamine B derivative-functionalized graphene quantum dots (RBD-GQDs) has been successfully synthesized for Fe³⁺ detection with high sensitivity and selectivity. By connecting with GQDs, the water solubility, sensitivity, photostability, and biocompatibility of RBD are drastically improved. The most distinctive feature of the RBD-GQDs, which sets them apart from other previously reported fluorophores or GQDs, is that they with the detection limits as low as 0.02 μM are demonstrated as a Fe³⁺ turn-on fluorescent nanosensor in cancer stem cells. Fe³⁺ binding to such GQDs (RBD-GQDs-Fe³⁺) with orange-red fluorescence of 43% quantum yield were demonstrated to be the biomarkers for cancer stem cell imaging

Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α‑Santonin Derivatives

As a therapeutic target for antitumor necrosis factor (TNF)-α interventions, UbcH5c is one of the key ubiquitin-conjugating enzymes catalyzing ubiquitination during TNF-α-triggered nuclear factor kappa B (NF-κB) activation. In the present study, three series of analogues were designed and synthesized from α-santonin, and their UbcH5c inhibitory activities were screened by Western blotting and NF-κB luciferase assay. Further BIAcore, in-gel fluorescence imaging, and immunoprecipitation assays demonstrated that compound <b>6d</b> exhibited robust and specific inhibition of UbcH5c, exceeding that of the positive compound <b>1</b> (IJ-5). Mechanistic investigations revealed that compound <b>6d</b> preferentially bound to and inactivated UbcH5c by forming a covalent adduct with its active site Cys85. Furthermore, compound <b>6d</b> exhibited potent anti-inflammatory activity against complete Freund’s adjuvant-induced adjuvant arthritis in vivo. These findings suggest that the novel α-santonin-derived UbcH5c inhibitor <b>6d</b> is a promising lead compound for the development of new antirheumatoid arthritis (RA) agent

Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α‑Santonin Derivatives

As a therapeutic target for antitumor necrosis factor (TNF)-α interventions, UbcH5c is one of the key ubiquitin-conjugating enzymes catalyzing ubiquitination during TNF-α-triggered nuclear factor kappa B (NF-κB) activation. In the present study, three series of analogues were designed and synthesized from α-santonin, and their UbcH5c inhibitory activities were screened by Western blotting and NF-κB luciferase assay. Further BIAcore, in-gel fluorescence imaging, and immunoprecipitation assays demonstrated that compound <b>6d</b> exhibited robust and specific inhibition of UbcH5c, exceeding that of the positive compound <b>1</b> (IJ-5). Mechanistic investigations revealed that compound <b>6d</b> preferentially bound to and inactivated UbcH5c by forming a covalent adduct with its active site Cys85. Furthermore, compound <b>6d</b> exhibited potent anti-inflammatory activity against complete Freund’s adjuvant-induced adjuvant arthritis in vivo. These findings suggest that the novel α-santonin-derived UbcH5c inhibitor <b>6d</b> is a promising lead compound for the development of new antirheumatoid arthritis (RA) agent