Synthesis of girinimbine and its derivatives and their anti- lung cancer activity

• Main Author: Osman, Fatin Nurul Atiqah
• Format: Thesis
• Language: English
• Published: 2017
• Subjects: Curry leaf tree - Therapeutic use; Murraya
• Online Access: http://psasir.upm.edu.my/id/eprint/69786/1/fs%202017%2090%20ir.pdf; http://psasir.upm.edu.my/id/eprint/69786/
• Institution: Universiti Putra Malaysia

Girinimbine (6) is a carbazole alkaloid which was first isolated from the stem bark of Murraya koenigii (curry plant). Girinimbine (6) has drawn an attention due to its wide range of pharmacological effects such as anti-platelet, anti-bacterial and anti-cancer activities. The aim of this study is to synthesize the girinimbine (6) and its derivatives by N-alkylation and N-acylation reactions. Two different routes were applied to produce 2-hydroxy-3-methylcarbazole (1), a precursor for the synthesis of girinimbine (6). The first route comprised of two steps to produce 1 via palladium-catalyzed coupling reaction between 1-bromo-2-nitrobenzene (45) and 4-iodo-2-methylphenol (46) to give 3-methyl-2'-nitrobiphenyl-4-ol (120), and followed by reduction of nitro group using dehydrated tin chloride. Meanwhile, the second route involved single step to produce 1 by using one pot coupling reaction between 1,2-dibromobenzene (47) and 5-amino-2-methylphenol (48). 2-Hydroxy-3-methylcarbazole (1) was then treated with 3-chloro-3-methyl-1-butyne to produce 3-methyl-2-[(2-methylbut-3-yn-2-yl)oxy]-9H-carbazole (121) and then refluxed in toluene to yield girinimbine (6). Five new derivatives of girinimbine (6) were successfully synthesised via semi-synthetic modification on N-terminal of naturally isolated girinimbine (6). N-benzylgirinimbine (122), N-butylgirinimbine (123) and N-isopentylgirinimbine (124) were obtained from alkylation reaction, whereas, N-butyrylgirinimbine (125) and N-methylbutyrylgirinimbine (126) were obtained from acylation reaction. The structures of synthesised girinimbine (6) and derivatives were confirmed by Fourier Transform Infrared Spectroscopy (FTIR), Gas Chromatography Mass Spectrometry (GCMS) and also Nuclear Magnetic Resonance (NMR). The structure of synthetic girinimbine (6) was also confirmed by comparison with the spectral data for the naturally isolated girinimbine (6). Compound 120 showed strong activity against lung cancer (A549) cell line with IC50 value of 17.0 μg/mL, while compound 121 and 123 exhibited strong activities through normal lung (MRC-5) cell line with IC50 values of 86.0 μg/mL and 96.1 μg/mL respectively. All girinimbine derivatives displayed moderate activities toward lung cancer (A549) cell line with IC50 values in range of 25-41 μg/mL. Compounds 120, 1 and 125 were the most potent anticancer agent with IC50 17.0-25.5 μg/mL (A549) and IC50 71.0-77.6 μg/mL (MRC-5).