ABSTRACT
Pancreatic cancer, which has an extremely poor prognosis, is one of the most fatal human cancers. Chemotherapy is the main palliative treatment for advanced cancer patients and also plays an indispensable role in postoperative treatments for surgical patients. Therefore, there is an urgent need to develop more innovative anticancer drugs to fight against this fatal disease. Here, we investigate the potential of benzophenone derivatives, obtained from a marine-derived strain of the fungus Pestalotiopsis neglecta, as antiproliferative lead compounds for the treatment of pancreatic cancer. The compounds, seven new (1-7) and two known (8 and 9) halogenated benzophenone derivatives, were obtained by bioactivity-guided fractionation from the cultures of Pestalotiopsis neglecta. The structures were defined by spectroscopic methods including X-ray crystallographic analysis. Using the commonly used pancreatic cancer cell line PANC-1, 2 and 4 were found to suppress cell proliferation and induce apoptosis in the low micromolar range of 7.6 and 7.2 µM, respectively. Mechanistically, benzophenone derivatives not only inhibit MEK activity in the cytoplasm but also suppress ERK activity in the cytoplasm and nucleus. An in silico study suggests that benzophenone derivatives could potentially inhibit MEK activity by binding to the allosteric pocket in MEK. Benzophenones could serve as new lead compounds for the treatment of pancreatic cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Benzophenones/pharmacology , Cell Proliferation/drug effects , MAP Kinase Signaling System/drug effects , Marine Biology , Pancreatic Neoplasms/pathology , Xylariales/chemistry , Antineoplastic Agents/chemistry , Benzophenones/chemistry , Benzophenones/isolation & purification , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Microbial Sensitivity Tests , Micrococcaceae/drug effects , Molecular Docking Simulation , Staphylococcus aureus/drug effectsABSTRACT
Four new meroterpenoids, austalides V-X (1-3) and a farnesylated phthalide derivative (4), were isolated from the culture of the marine fungus Penicillium rudallense, together with eight known meroterpenoids derivatives (5-12). Their structures, including absolute configurations, were determined by spectroscopic methods. All of the isolated compounds were evaluated for their inhibitory activities on the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation. Compounds 1, 2, 5-7, and 10 exhibited potent osteoclast differentiation inhibitory activity with ED50 values of 1.9-2.8 µM.
Subject(s)
Bone Density Conservation Agents/chemistry , Bone Density Conservation Agents/pharmacology , Osteoclasts/drug effects , Penicillium/chemistry , Terpenes/chemistry , Terpenes/pharmacology , Animals , Cell Differentiation/drug effects , Fermentation , Mice , Mice, Inbred ICR , Molecular Structure , RANK Ligand/drug effects , Seawater/microbiologyABSTRACT
Activity-guided fractionations of the tunicate Pseudodistoma antinboja yielded four new compounds of the cadiolide class (cadiolides J-M, 1, 3-5) along with a known one (cadiolide H, 2). The structures were defined by spectroscopic methods including X-ray crystallographic analysis. These compounds were evaluated for their antibacterial activity and exhibited potent antibacterial activity against all of the drug resistant strains tested with MICs comparable to those of marketed drugs such as vancomycin and linezolid.
