ABSTRACT
Resveratrol is a natural (poly)phenol primarily found in plants protecting them against pathogens, as well as harmful effects of physical and chemical agents. In higher eukaryotic cells and organisms, this compound displays a remarkable range of biological activities, such as anti-oxidant, anti-inflammatory, anti-cancer, anti-aging, cardio- and neuro-protective properties. Here, biological activities of synthetic selenium-containing derivatives of resveratrol-benzo[b]selenophenes-have been studied in lower eukaryotes Saccharomyces cerevisiae. Their toxicity, as well as DNA damaging and reactive oxygen species (ROS) inducing potencies, manifested through their ability to act as redox active anti-microbial agents, have been examined. We show that some benzo[b]selenophenes can kill yeast cells and that the killing effects are not mediated by DNA damage types that can be detected as DNA double-strand breaks. These benzo[b]selenophenes could potentially be used as anti-fungal agents, although their concentrations relevant to application in humans need to be further evaluated. In addition, most of the studied benzo[b]selenophenes display redox-modulating/anti-oxidant activity (comparable or even higher than that of resveratrol or Trolox) causing a decrease in the intracellular ROS levels in yeast cells. Therefore, after careful re-evaluation in other biological systems these observations might be transferred to humans, where resveratrol-inspired benzo[b]selenophenes could be used as supra-anti-oxidant supplements.
Subject(s)
Antioxidants/chemistry , Antioxidants/pharmacology , Organoselenium Compounds/chemistry , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/metabolism , Stilbenes/chemistry , Stilbenes/pharmacology , DNA Breaks, Double-Stranded/drug effects , DNA Damage/drug effects , Microbial Viability/drug effects , Molecular Structure , Reactive Oxygen Species/metabolism , ResveratrolABSTRACT
The cyclization of arylalkynes under selenobromination conditions, combined with an acid-induced 3,2-aryl shift, was elaborated as a general synthetic pathway for the preparation of polyhydroxy-2- and -3-arylbenzo[b]selenophenes from the same starting materials. The redox properties, free-radical-scavenging ability, and cytotoxicity against malignant cell lines (MCF-7, MDA-MB-231, HepG2, and 4T1) of the synthesized compounds were explored, and the obtained results were used to consider the structure-activity relationships (SARs) in these compounds. Consequently, the structural features that were responsible for the highly potent peroxyl-radical-scavenging activity were established.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Organoselenium Compounds/chemistry , Organoselenium Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antioxidants/chemical synthesis , Benzene Derivatives/chemical synthesis , Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclization , Humans , Neoplasms/drug therapy , Organoselenium Compounds/chemical synthesis , Oxidation-Reduction/drug effectsABSTRACT
Synthetic protocols for the preparation of selenium analogues of raloxifene were elaborated. General aim of the current research is to improve the positive impact of selenium atom introduction in drug design. Antiproliferative activity on CCL-8 (mouse sarcoma), MDA-MB-435s (human melanoma), MES-SA (human uterus sarcoma), MCF-7 (human breast adenocarcinoma), HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma) tumor cell lines, and normal cell line NIH 3T3 (mouse fibroblasts) was studied. Influence of aminoethoxy "tail" and benzoyl group position on SAR was discussed. Results of in vivo studies on BALB/c female mice with 4T1 cell induced breast cancer model showed that selenium analogue of raloxifene is able to suppress estrogen-depending tumor growth.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Raloxifene Hydrochloride/analogs & derivatives , Selenium/chemistry , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Female , Humans , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred BALB C , NIH 3T3 Cells , Raloxifene Hydrochloride/pharmacology , Spectrometry, Mass, Electrospray IonizationABSTRACT
Synthesis, molecular structure and cytotoxic activity of a series of 3-C, N, S, Se substituted benzo[b]selenophene derivatives on human fibrosarcoma HT-1080, mouse hepatoma MG-22A, and mouse fibroblasts 3T3 cell lines are described. The correlation between compound LD(50) 3T3 fibroblast cell line and HT-1080 morphology was shown.
