title: Discovery of a novel series of tetrahydro-β-carbolines inducing autophagic cell death in human metastatic melanoma.
abstract: Herein, we report the synthesis of novel tetrahydro-β-carbolines that induce cell death via the autophagic pathway. Five of the new compounds induced cell death in a panel of patient-derived human metastatic melanoma cells. The autophagic pathway was confirmed using LC3 autophagosome markers; the involvement of ATG7 and Beclin 1 autophagy regulating genes was confirmed using infection with short hairpin RNA (shRNA) to silence Beclin 1 and ATG7. Compound VIII (IC50  = 2.34-5.15 μM) displayed activities greater than cisplatin against a panel of patient-derived human metastatic melanoma cell lines. The structure-activity relationship (SAR) of this class and the role of the absolute stereochemistry and geometrical isomerism are evaluated.
authors.affiliation: Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, Cairo, Egypt.
authors.forename: Nermin S
authors.initials: NS
authors.lastname: Ahmed
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elgendy
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D007536:Isomerism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D015394:Molecular Structure; D034622:RNA Interference; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013329:Structure-Activity Relationship; D014162:Transfection; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D002243:Carbolines; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C009804:tryptoline; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D002945:Cisplatin
keywords: Anticancer; Autophagy; Melanoma; Non-planar; Tetrahydro-β-carbolines