title: Synthesis of novel tetrahydrobenzazepine derivatives and their cytoprotective effect on human lymphocytes.
abstract: Cytoprotective compounds such as amifostine play an important role in chemo- and radiotherapy due to their ability to reduce the side effects of these treatments. Our work was initiated with the intention to design, synthesise and test a new class of heterocyclic compounds that would have an antioxidative profile with the potential to be further developed as cytoprotective agents. The design was based on the privileged tetrahydrobenzazepine scaffold found in many natural products with a wide range of biological properties. This structure was further functionalised with moieties known to possess antioxidative features such as tertiary amine and styrene double bond. A series of eight tetrahydrobenzazepine derivatives of isoquinoline, 3,4-dihydro-β-carboline and pyridine were synthesised employing the Heck reaction as a key transformation. Some of the prepared compounds were tested for their in vitro effects on chromosome aberrations in peripheral human lymphocytes using the cytochalasin-B blocked micronucleus (MN) assay. Three tetrahydrobenzoazepine derivatives showed significant cytoprotective properties, comparable or even better to those of the radioprotective agent amifostine.
authors: Faculty of Pharmacy, Department of Organic Chemistry, University of Belgrade, Belgrade, Serbia.
authors: Milena R
authors: MR
authors: Simic
authors: Miroslava
authors: M
authors: Stankovic
authors: Boris M
authors: BM
authors: Mandic
authors: Vele V
authors: VV
authors: Tesevic
authors: Vladimir M
authors: VM
authors: Savic
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D004999:Amifostine / Q000494:pharmacology; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology*; D001552:Benzazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D003571:Cytochalasin B / Q000633:toxicity; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced / Q000187:drug effects*; D015162:Micronucleus Tests; D016685:Mitomycin / Q000633:toxicity; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000477:Alkylating Agents; D000975:Antioxidants; D001552:Benzazepines; D011837:Radiation-Protective Agents; D003571:Cytochalasin B; D016685:Mitomycin; D004999:Amifostine
keywords: Cytoprotection; Heterocycles; Micronuclei; Synthesis; Tetrahydrobenzazepine