Synthesis, characterization and ROS-mediated cytotoxic action of novel (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid and corresponding esters.
This study involves the synthesis and characterization of novel cyclohexyl 1,3-propanediamine-N,N'-diacetate molecules as well as investigation of their cytotoxic action. New acid 1a was synthesized by reaction between (S)-2-amino-3-cyclohexylpropanoic acid and 1,3-dibromopropane, while the esters (1b-1e) derived from this acid were obtained by reaction of the corresponding absolute alcohol, thionyl chloride and synthesized acid. All compounds were characterized by IR, ESI-MS, ((1)H, (13)C and HSQC) NMR spectroscopy and elemental analysis. The cytotoxic activity of all compounds was tested on several tumour cell lines: human (U251) and rat (C6) glioma, human promyelocytic leukaemia (HL-60), human neuroblastoma (SHSY-5Y) and mouse fibrosarcoma (L929) as well as primary rat astrocytes. The present study reveals potent antitumour activity of novel purely organic compounds (1a-1e), which was most pronounced in human glioma (U251) cells. The esterification is required for the novel compounds' cytotoxic action since the n-butyl ester 1e was the most efficient compound. Importantly, n-butyl ester 1e was more toxic to glioma cells in comparison to rat astrocytes, with 24-h IC50 values lower than those for cisplatin. n-Butyl ester 1e induced production of reactive oxygen species (ROS) and caused an oxidative-stress-derived accumulation of glioma cells in the G0/G1 phase of the cell cycle, as well as caspase activation and DNA fragmentation, suggesting that apoptosis induction plays an important role in the novel compounds' antiglioma action.
Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
Aleksandar
A
Savić
Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Sonja
S
Misirlić-Denčić
Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Marija
M
Dulović
Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
Ljiljana E
LE
Mihajlović-Lalić
Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Maja
M
Jovanović
Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia. Electronic address: sanjag@chem.bg.ac.rs.
Sanja
S
Grgurić-Šipka
Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: ivanka@med.bg.ac.rs.
Ivanka
I
Marković
Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
Tibor J
TJ
Sabo
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004952:Esters; C000596492:O,O'-dibutyl-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoate; D017382:Reactive Oxygen Species; D000409:Alanine
Amine ligands; Apoptosis; Cyclohexyl analogues; Cytotoxic activity; Oxidative stress; n-Butyl ester