Selective cytotoxicity of dihydroorotate dehydrogenase inhibitors to human cancer cells under hypoxia and nutrient-deprived conditions

Human dihydroorotate dehydrogenase (HsDHODH) is a key enzyme of pyrimidine de novo biosynthesis pathway. It is located on the mitochondrial inner membrane and contributes to the respiratory chain by shuttling electrons to the ubiquinone pool. We have discovered ascofuranone (1), a natural compound produced by Acremonium sclerotigenum, and its derivatives are a potent class of HsDHODH inhibitors. We conducted a structure–activity relationship study and have identified functional groups of 1 that are essential for the inhibition of HsDHODH enzymatic activity. Furthermore, the binding mode of 1 and its derivatives to HsDHODH was demonstrated by co-crystallographic analysis and we show that these inhibitors bind at the ubiquinone binding site. In addition, the cytotoxicities of 1 and its potent derivatives 7, 8, and 9were studied using human cultured cancer cells. Interestingly, they showed selective and strong cytotoxicity to cancer cells cultured under microenvironment (hypoxia and nutrient-deprived) conditions. The selectivity ratio of 8 under this microenvironment show the most potent inhibition which was over 1000-fold higher compared to that under normal culture condition. Our studies suggest that under microenvironment conditions, cancer cells heavily depend on the pyrimidine de novo biosynthesis pathway. We also provide the first evidence that 1 and its derivatives are potential lead candidates for drug development which target the HsDHODH of cancer cells living under a tumor microenvironment

Superior vena cava syndrome caused by mediastinal recurrence of breast cancer with a 13-year disease-free interval: A case report

　Superior vena cava syndrome (SVCS) is an oncological emergency. Lung cancer is the most causative malignancy. In contrast, breast cancer rarely causes SVCS. We report a case in which SVCS was caused by mediastinal lymph node metastasis of breast cancer. The patient was a 60-year-old woman who had undergone breast-conserving therapy at another hospital 13 years previously. Her breast cancer was early stage T1a(5mm)N0M0; Stage IA), and Luminal type (HER2 negative). She had received adjuvant hormone therapy, but dropped out of treatment two years and six months later. Recently, she had developed cough and face edema, and her extrajugular vein was swollen. CT revealed swollen mediastinal and supraclavicular lymph nodes, lung nodules, pericardial effusion, right pleural fluid, and stenosis of the superior vena cava (SVC). She was diagnosed with recurrent breast cancer with SVCS due to mediastinal LN swelling. A core needle biopsy of a supraclavicular lymph node revealed metastasis; the diagnosis was luminal HER2 positive breast cancer. We initiated treatment with radiotherapy for the mediastinal lymph nodes, and then started hormone therapy and anti-HER2 therapy. These therapies provided relief from her symptoms. She is currently alive and continuing hormone therapy and anti-HER2 therapy. In cases of SVCS due to malignancy, the biopsy findings should be taken into account when possible. An accurate diagnosis is extremely important for the suitable treatment of SVCS, especially in cases caused by malignancy

Synthesis of Tetra‐Substituted Trifluoromethyl‐3,1‐Benzoxazines by Transition‐Metal‐Catalyzed Decarboxylative Cyclization of N‐Benzoyl Benzoxazinones

Abstract Efficient synthesis of N,O‐heterocyclic tetra‐substituted trifluoromethyl‐3,1‐benzoxazines via a transition‐metal‐catalyzed decarboxylative intramolecular cyclization was achieved. The decarboxylation of N‐benzoyl trifluoromethyl‐benzoxazinones generated the amide oxygen nucleophile, allowing a selective internal C1‐attack on Pd‐ or Cu‐coordinated zwitterions, affording medicinally attractive tetra‐substituted vinyl‐ or ethynyl‐trifluoromethyl‐3,1‐benzoxazines. This protocol can be applied to the synthesis of perfluoroalkyl‐ and non‐fluorinated 3,1‐benzoxazines

Radiation induced chromosomal instability in peripheral blood lymphocytes obtained from breast cancer patients.

International Symposium on Biological Effects of Low Dose Radiation: Molecular Mechanisms for Radiation-induced Cellular Response and Cancer Developmen