ABSTRACT
A 6-year-old intact female sugar glider (Petaurus breviceps) had a swelling at the pouch region and died 8 days after presentation. At necropsy, the urinary bladder and abdominal lymph nodes were enlarged and a mass was located in the pericloacal region. Tumour infiltration was also observed in the medial iliac lymph nodes, liver, spleen, small intestine, uterus and left ovary. Histopathologically, the tumours were composed of pleomorphic histiocytes that had round or bizarre nuclei and abundant pale eosinophilic cytoplasm. Immunohistochemically, tumour cells were positive for ionized calcium-binding adaptor molecule 1 and human leukocyte antigen and negative for CD3, B lymphocyte antigen 36 and cytokeratin. Histopathological and immunohistochemical examinations confirmed a diagnosis of disseminated histiocytic sarcoma. This neoplasm has not been previously reported in a sugar glider.
Subject(s)
Histiocytic Sarcoma , Marsupialia , Animals , Fatal Outcome , Female , Histiocytes , Histiocytic Sarcoma/veterinary , SkinSubject(s)
Drug Resistance, Microbial , Helicobacter Infections/drug therapy , Helicobacter pylori/drug effects , Peptic Ulcer/drug therapy , Amoxicillin/therapeutic use , Child , Child, Preschool , Clarithromycin/therapeutic use , Drug Therapy, Combination , Female , Gastritis/microbiology , Helicobacter Infections/epidemiology , Helicobacter pylori/genetics , Humans , Levofloxacin/therapeutic use , Male , Metronidazole/therapeutic use , Peptic Ulcer/microbiology , Tetracycline/therapeutic use , Vietnam/epidemiologyABSTRACT
BACKGROUND: Target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development worldwide, and Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as vorinostat and belinostat. AIMS: This study aims at developing novel HDAC inhibitors bearing quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines. METHODS: A series of novel N-hydroxyheptanamides incorporating 6-hydroxy-2 methylquinazolin-4(3H)-ones (14a-m) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2 (liver cancer), MCF-7 (breast cancer) and SKLu-1 (lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. ADME-T predictions for selected compounds were also performed to predict some important features contributing to the absorption profile of the present hydroxamic derivatives. RESULTS: It was found that the N-hydroxyheptanamide 14i and 14j were the most potent, both in terms of HDAC inhibition and cytotoxicity. These compounds displayed up to 21-71-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in terms of cytotoxicity, and strong inhibition against the whole cell HDAC enzymes with IC50 values of 7.07-9.24µM. Docking experiments on HDAC2 isozyme using Autodock Vina showed all compounds bound to HDAC2 with relatively higher affinities (from -7.02 to -11.23 kcal/mol) compared to SAHA (-7.4 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward breast cancer cells (MCF-7) than liver (HepG2), and lung (SKLu-1) cancer cells.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Histone Deacetylase 2/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Quinazolines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Hep G2 Cells , Histone Deacetylase 2/metabolism , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , MCF-7 Cells , Molecular Docking Simulation , Molecular Structure , Quinazolines/chemistry , Structure-Activity RelationshipABSTRACT
Four new polyoxygenated sterol derivatives (1-4) along with the compounds (5-7) previously known from other biological sources were isolated from the gorgonian Menella woodin, collected from the Vietnamese waters. Structures of 1-4 were elucidated by the detailed NMR spectroscopic and mass-spectrometric analyses as well as comparison with those reported in literature data. Compounds 1, 4, and 6 decrease the production of reactive oxygen species (ROS) by the murine macrophages of RAW 264.7 line at induction by endotoxic lipopolysaccharide (LPS) from Escherichia coli.
Subject(s)
Anthozoa/chemistry , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Reactive Oxygen Species/metabolism , Steroids/pharmacology , Animals , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Mice , Molecular Conformation , Reactive Oxygen Species/antagonists & inhibitors , Steroids/chemistry , Steroids/isolation & purification , Structure-Activity RelationshipABSTRACT
Eight new oxidized lanostane and nor-lanostane derivatives (1-8) along with the previously known penasterol (9) and 24-ethylcholesta-4,24(28)-dien-3-one (10) were isolated from a sponge Penares sp. collected from the Vietnamese waters. Structures of these minor compounds were elucidated by the detailed NMR spectroscopic and mass-spectrometric analyses and by comparison with earlier reported spectroscopic data. A hypothetic scheme of metabolism of the lanostane derivatives in sponges belonging to Penares and Erylus genera was proposed and discussed.
