title: Synthesis and biological screening for cytotoxic activity of N-substituted indolines and morpholines.
abstract: Development of novel anticancer drugs is inevitable to improve treatment of cancers. In this study, novel derivatives of indoline and morpholine were synthesized and tested for their cytotoxic effects on osteosarcoma and Human Embryonic Kidney cells. To characterize cytotoxicity and the mechanism of cell death, we used cytotoxicity, migration, apoptosis markers and mitochondrial calcium assays. Among the compounds tested, the indoline derivatives, generally, produced a higher cytotoxic effect compared to the morpholine derivatives, in osteosarcoma cells. Specifically, new indoline derivative N-(2-hydroxy-5-nitrophenyl(4'-methylphenyl)methyl)indoline exhibited effective cytotoxic activity, with an IC50 of ∼74 μM. The same molecule induced cell death by apoptosis and inhibited migration of the cells. Further, analysis of mitochondrial calcium levels revealed the existence of calcium dependent cell death mechanisms in different cell types. Therefore, N-(2-hydroxy-5-nitrophenyl(4'-methylphenyl)methyl)indoline can be considered as a potential drug-lead compound towards the discovery of new anti-cancer agents.
authors.affiliation: Molecular Signaling Lab, Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland.
authors.forename: Phuong
authors.initials: P
authors.lastname: Doan
authors.affiliation: Molecular Signaling Lab, Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland.
authors.forename: Anzhelika
authors.initials: A
authors.lastname: Karjalainen
authors.affiliation: Molecular Signaling Lab, Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland.
authors.forename: Jerome G
authors.initials: JG
authors.lastname: Chandraseelan
authors.affiliation: Molecular Signaling Lab, Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland.
authors.forename: Ossi
authors.initials: O
authors.lastname: Sandberg
authors.affiliation: Molecular Signaling Lab, Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland; Institute for Systems Biology, 1441N 34th Street, Seattle, WA 98103-8904, USA.
authors.forename: Olli
authors.initials: O
authors.lastname: Yli-Harja
authors.affiliation: Department of Chemistry and Bioengineering, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland.
authors.forename: Tomi
authors.initials: T
authors.lastname: Rosholm
authors.affiliation: Department of Chemistry and Bioengineering, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland.
authors.forename: Robert
authors.initials: R
authors.lastname: Franzen
authors.affiliation: Department of Chemistry and Bioengineering, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland. Electronic address: nuno.rafaelcandeias@tut.fi.
authors.forename: Nuno R
authors.initials: NR
authors.lastname: Candeias
authors.affiliation: Molecular Signaling Lab, Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, P.O. Box 553, 33101 Tampere, Finland. Electronic address: meenakshisundaram.kandhavelu@tut.fi.
authors.forename: Meenakshisundaram
authors.initials: M
authors.lastname: Kandhavelu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D012516:Osteosarcoma / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009025:Morpholines; C057812:indoline
keywords: Anticancer; Apoptosis induction; Cytotoxicity; Indoline; Morpholine