Discovery of naphthacemycins as a novel class of PARP1 inhibitors.

Poly (ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear protein that plays important roles in a variety of nuclear processes, and it has been proved a prominent target in oncology for its key function in DNA damage repair. In this study, we discovered a series of naphthacemycins as a new class of PARP1 inhibitors from a microbial metabolites library via high-throughput screening. Compound I, one of this series of compounds, could reduce cellular poly (ADP-ribose) level, trap PARP1 on the damaged DNA and elevate the level of γ-H2AX, and showed the selective cytotoxicity against BRCA1-deficient cell line. Our study provided a potential scaffold for the development of new PARP1 inhibitors in cancer therapy.

Complex carotid artery stenosis via enhanced anterior cervical triangle posterior vena jugularisinterna approach.

The paper discuss the surgical techniques and clinical curative effects of CEA (Carotid Endarterectomy, CEA) under a microscope via anterior cervical triangle posterior vena jugularisinterna approach combining with suspended carotid artery on the treatment of high level and complex carotid artery stenosis. Retrospective analysis was conducted on the clinical data of 21 cases of patients. The far end of carotid artery stenosis section is located above the lower edge of the second cervical vertebra centrum. The carotid artery stenosis section of three cases is located at the middle lower edge of the first cervical vertebrae. Clinical evaluation was performed from surgical process, time of postoperative drainage tube removal, perioperative complications and follow-up survey on the serious numbness at the surgical site one month, three months and six months after the surgery. There are 0 cases of postoperative death, 0 cases of cerebral hemorrhage cerebral infarction, 1 case of myocardial infarction, 2 cases of Hypoglossal nerve temporary injury, 0 case of infection of incisional wound and incidence rates of serious numbness in postoperative follow-up surgical area one month, 3 months and 6 months are 23.81%, 19.05% and 9.52% respectively. The cranial nerves and surrounding muscle groups at the far end of carotid artery stenosis and carotid artery can be fully disposed via anterior cervical triangle posterior vena jugularisinterna by utilizing microsurgery-technique and suspended carotid artery technology conveniently and completely to avoid cutting the corresponding branches of vena jugularisinterna and too much anatomy of anterior triangle lymph fatty tissue to properly avoid postoperative edema at the surgical area, cranial nerve injuries and other complications. It is a convenient, efficient, safe and effective CEA approach. .

Angucyclinones with IDO and TDO inhibitory activities isolated from the actinomycetes Umezawaea beigongshangensis.

Four previously undescribed angucyclinones umezawaones A-D (1-4) were isolated from the liquid cultures of Umezawaea beigongshangensis. Their structures were determined by spectroscopic analyses, single crystal X-ray diffraction, quantum chemical 13C NMR and electronic circular dichroism calculations. All compounds displayed strong inhibitory activities against indoleamine 2,3-dioxygenase and tryptophan-2,3-dioxygenase in enzymatic assay, especially compound 2.

[F01WB-1315 A and B, two dihydroorotate dehydrogenase inhibitors from microbial metabolites].

OBJECTIVE: Dihydroorotate Dehydrogenase (DHODH) catalyzes the rate-limiting step in pyrimidine biosynthesis, and its inhibitors have been developed as drugs for treatment of immune diseases. We studied new DHODH inhibitors from microbial metabolites. METHODS: We established a rapid and effective high throughput screening method for screening DHODH inhibitors from microbial metabolites. The active compounds were isolated from the candidate strain by column chromatography and preparative HPLC. RESULTS: We picked out F01WB-1315 strain as candidate from 4560 fungal strains. We isolated two active compounds F01WB-1315A and B, with IC50 of 0.07 microg/mL and 0.51 microg/mL, respectively. F01WB-1315B could completely inhibit the spleen lymphocytes proliferation stimulated by ConA in vitro, but F01WB-1315A only had 31.62% inhibitory activity. F01WB-1315A, B were identified to be Ascofuranone and Ascochlorin by their physicochemical properties, MS, 13C-NMR and 1H-NMR analysis. CONCLUSION: F01WB-1315A and B are two strong specific DHODH inhibitors and show moderate inhibitory activity against spleen lymphocytes proliferation.

Discovery of a new structural class of competitive hDHODH inhibitors with in vitro and in vivo anti-inflammatory, immunosuppressive effects.

Human dihydroorotate dehydrogenase (hDHODH) is an inner mitochondrial membrane enzyme that involves in the fourth step of the biosynthesis of pyrimidine base. Inhibitors of hDHODH have been proven efficacy for the treatments of inflammation, rheumatoid arthritis, multiple sclerosis and cancer. In the present study, ascochlorin (ASC) and its derivatives, natural compounds from fungal metabolites, were discovered as hDHODH inhibitors by high-throughput screening. Enzyme kinetics studies showed that ASC competitively binds to hDHODH at the site of coenzyme Q substrate. In ex vivo study, ASC significantly inhibited the ConA-stimulated T lymphocytes proliferation and interleukin-2, interferon-γ production. Furthermore, ASC showed significant in vivo anti-inflammatory and immunosuppressive effects on the mice ears swelling, allogenic skin grafts and rat collagen-induced arthritis animal disease models. ASC significantly reduced ears edema level of mice, increased the survival time of allogenic skin implanted on the mice and attenuated arthritis severity of rat model. In conclusion, ASC was identified as a new structural class of hDHODH inhibitors with efficient anti-inflammatory, immunosuppressive activity, and may be a promising candidate for the development of new therapy in the treatment of autoimmune diseases.

Three novel members of angucycline group from Streptomyces sp. N05WA963.

Three novel members of angucycline family named N05WA963A (1), B (2) and D (4), together with a new anthracycline named N05WA963C (3) were isolated from the culture broth of Streptomyces sp. N05WA963. The structures were elucidated on the basis of comprehensive spectral data analysis. All four compounds have shown antiproliferative effects on a panel of cancer cell lines such as SW620, K-562, MDA-MB-231, YES-4, T-98 and U251SP.