ChemBioChem

Design, Synthesis, and Biological Evaluation of New Urushiol Derivatives as Potent Class I Histone Deacetylase Inhibitors

AbstractIn the present study, a novel series of 11 urushiol‐based hydroxamic acid histone deacetylase (HDAC) inhibitors was designed, synthesized, and biologically evaluated. Compounds 1–11 exhibited good to excellent inhibitory activities against HDAC1/2/3 (IC50: 42.09–240.17 nM) and HDAC8 (IC50: 16.11–41.15 nM) in vitro, with negligible activity against HDAC6 (>1409.59 nM). Considering HDAC8, docking experiments revealed some important features contributing to inhibitory activity. According to Western blot analysis, select compounds could notably enhance the acetylation of histone H3 and SMC3 but not‐tubulin, indicating their privileged structure is appropriate for targeting class I HDACs. Furthermore, antiproliferation assays revealed that six compounds exerted greater in vitro antiproliferative activity against four human cancer cell lines (A2780, HT‐29, MDA‐MB‐231, and HepG2, with IC50 values ranging from 2.31–5.13 μM) than suberoylanilide hydroxamic acid; administration of these compounds induced marked apoptosis in MDA‐MB‐231 cells, with cell cycle arrest in the G2/M phase. Collectively, specific synthesized compounds could be further optimized and biologically explored as antitumor agents.

A Dual Bispecific Hydrolysis Peptide‐Drug Conjugate Responsive to Micro‐Acidic and Reduction Circumstance Promotes Antitumor Efficacy in Triple‐Negative Breast Cancer

AbstractPaclitaxel and its derivates are the first‐line chemotherapeutic agents of breast cancer, which also showed tremendous clinical value in many other diseases including ovarian cancer, lung cancer etc. However, there are many drawbacks for almost all paclitaxel or its derivates, including extremely short half‐life, poor solubility and adverse events, which significantly limits their clinical applications. In this work, we designed and constructed a bispecific hydrolysis PAP‐SS‐PTX (term as PDC), consisting with pro‐apoptosis peptide (PAP) and paclitaxel (PTX) that were conjugated together via disulfide and ester bonds. On the one hand, PAP could improve the solubility of PTX and promote cellular uptake for drugs. On the other hand, it was able to prolong the PTX half‐life. We performed series of chemo‐dynamical assays and showed that PDC would release active drug molecules under micro‐acidic and reduction circumstance. The further assays elucidated that PDC could interrupt DNA synthesis and arrest cell division through downregulating CDK4/6 and Histone methylation that inhibit tumor growth in vitro. What's more, it could not only inhibit 4T1 breast tumor growth, but also prolong the survival time of mice and exert antitumor efficacy in vivo. It may provide a new research idea for cancer therapies via controlled release strategy in tumor microenvironment.

Nonmetal Methoxy‐Porphyrin Nanophotosensitizers: An Antitumor Agent for Photodynamic Therapy against Breast Cancer and Cervical Cancer

With the continuous development of precision medicine and personalized treatment, traditional therapeutic approaches such as surgery, chemotherapy, and radiotherapy are increasingly unable to meet the ever‐changing clinical needs. Therefore, developing highly efficient, low‐toxicity, and well‐targeted treatment strategies has become an urgent priority in cancer therapy. Photodynamic therapy (PDT) has made significant strides in tumor treatment in recent years. Among the various materials used in PDT, porphyrin photosensitizers have emerged as one of the most utilized options due to their exceptional photodynamic activity, excellent targeting ability, low toxicity, and versatility. Here, this study selects nonmetal methoxy‐porphyrin nanophotosensitizers as high‐performance antitumor materials. Both in vitro and in vivo analyses demonstrate that these nanophotosensitizers efficiently generate reactive oxygen species, exhibiting significant cytotoxic effects at the cellular level. In tumor‐bearing mouse models using 4T1 and HeLa cells, they show remarkable tumor inhibition, confirming their therapeutic potential in breast and cervical cancer models. Transcriptomic sequencing further reveals their regulatory roles in tumor‐related signaling pathways. Overall, these findings highlight the exceptional antitumor properties of nonmetal methoxy‐porphyrin nanophotosensitizers and provide foundational evidence for their application in PDT for gynecological malignancies.

Anticancer Water‐Soluble Organoruthenium Complexes: Synthesis and Preclinical Evaluation

AbstractThe synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate‐based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non‐small‐cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18‐electron complexes were designed with four water‐soluble phosphine ligands to increase the water‐solubility character of the corresponding electron‐deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine‐3,3′,3′′‐trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16‐electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on reactive oxygen species (ROS) production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay.