Design, Synthesis, Cytotoxic Activity And DNA Intercalation Of New β-Carboline Derivatives
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Date
2018-06
Authors
Mohideen, Mazlin
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Journal ISSN
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Publisher
Universiti Sains Malaysia
Abstract
The focus of this study has been to investigate the in vitro cytotoxic effects of new β-carboline derivatives on the K562 human cancer cell line. Analysis using 3D-QSAR models has revealed the importance of derivatisation at position-2 and -9 of the β-carbolines. Two new series of N2-benzylated-β-carboline (M23-M46) and N2-N9-benzylated-1-substituted-β-carboline derivatives (M47-M113) were synthesised and characterised using four-step reaction and were produced in good yields (>70%). Compounds M23-M113 exhibited the most potent anticancer activity with IC50 values between 0.01-4 μM, except for compounds M88-M90 which produced IC50 values of more than 100 μM. Six of N2-N9-benzylated-1-substituted-β-carboline derivatives (M53, M85, M86, M104, M109 and M112) showed IC50 values between 0.01-0.07 μM when compared to doxorubicin (DOX) which was employed as the positive control (0.77 μM). The structure-activity relationships (SARs) study has revealed that additional substituents of the benzyl group at position-2 and -9 exhibited the most interesting cytotoxic activities. Intercalator agents such as DOX, harmine (HAR), 5-fluorouracil (5-FU) and selected -carboline derivatives M53 and M56 were used as the model compounds. The intercalating mechanism was explored using calf thymus DNA (CT-DNA) as a model system. UV-Vis showed that DOX, HAR, M53 and M56 induced hypochromic effect and redshift, while 5-FU did not. In fluorescence emission, fluorescence quenching was observed in the EtBr-DNA system (probe) upon addition of DOX, HAR, 5-FU, M53 and M56. In circular dichroism (CD), DOX and HAR changed the intensities of the positive and negative bands of DNA in the same direction while compounds M53 and M56 induced the opposite change.
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Keywords
Effects of new β-carboline derivatives on , the K562 human cancer cell line