Isolation And Selective Reduction Of Mitragynine, Synthesis And Characterization Of New Indole Derivatives And Their Selected Biological Activity Studies
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Date
2015-09
Authors
Goh, Teik Beng
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Abstract
Mitragynine (MTG) possesses potent analgesic properties but the toxic effects of MTG have also been reported. The main objective of this thesis is to isolate MTG for further structural modification and also to synthesize its indole derivatives and evaluate their antiproliferative, antioxidant and antinociceptive activities. MTG was isolated from M. speciosa leaves using a simple and effective purification procedure. Various silanes were used to reduce the carbonyl and indole double bonds of MTG but only the indole double bond was successfully reduced to indoline [CDR80 ((E)-methyl 2-((2S,3S,12bS)-3-ethyl-8-methoxy-1,2,3,4,6,7,7a,12,12a,12b-decahydroindolo[2,3-a]quinolizin-2-yl)-3-methoxy acryl ate)]. The Pictet-Spengler reaction was modified using 5-methoxytryptamine and trifluoroacetic acid in an aqueous medium to synthesize new indole derivatives which were identified and characterized as CDR81 (6- methoxy-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole), CDR82 (6-methoxy-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole), CDR83 (6-methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole) and CDR84 (2-methoxy-4-(6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indol-1-l)phenol). The absolute configuration of C-1 was determined as S using NMR analysis, CD (circular dichroism) spectra analysis and single crystal data analysis with reference to Cahn-Ingold priority rule. Four new indole derivatives, namely CDR81, CDR82, CDR83 and CDR84 were evaluated on a panel of human cancer cell line namely HT 29, K 562, HCT 116, MCF-7, CEM SS, HEPG2, SH-5YSY, MDA-MB-231 and HELA. In addition, CDR80 and MTG were tested against K 562 and HCT 116 cell lines. CDR82 was found to be the most active derivative, with good selectivity on the K 562, HCT 116 and HT29 cancer cell lines as compared to the non-tumorous cell lines of NIH/3T3, CCD18-Co and B98-5. In addition, CDR82 showed better activity and selectivity than the standard anticancer drugs cisplatin, betulinic acid and 5-fluorouracil on the HT29 (SI=3.89), K 526 (SI=8.71) and HCT116 (SI=5.68) cancer cell lines respectively. CDR81 was the second most active, CDR83 showed only mild activity while CDR84 has no activity. The indole derivatives were found to exhibit moderate anti-oxidative properties, based on a combination of DPPH, ABTS and reducing power assays. CDR84 showed the highest antioxidant activity due to both indole and phenolic groups in its structure whilst other β-carboline derivatives do not have the phenolic group. However, none of these derivatives showed the central analgesic activity exhibited by mitragynine.
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Medicine