Abstract
Background: Direct N-alkylation of murrayafoline A (1) by epichlorohydrin, followed by the opening of 3-(1-methoxy-3-methyl-N-carbazolyl)-1,2-epoxypropane (2) with aliphatic and heterocyclic amines catalyzed by Zn(HClO4)2 .6H2O in mild condition led to the formation of thirteen β-amino alcohols (6a-n) in moderate yields. In vitro anticancer activity of these β-amino alcohols (6a-n) was evaluated against four human cancer cell lines including Hep-G2, LU-1, P 338 and SW 480 in comparison with murrayafoline A. The results showed that the synthesized β-amino alcohols (6a-n) (excluding 6e, 6n.1) inhibited proliferation of cancer cell lines and compound 6c was found to have the best activity against Hep-G2 and LU-1 with IC50 values of 3.99 and 4.06 μg/mL, respectively.
Methods: All chemicals and reaction solvents were purchased from Merck and Aldrich. Melting points were determined in open capillaries on a Shimazu Electrothermal IA 9200 apparatus and are uncorrected. IR spectra were recorded on a FT-IR IMPACT-410 using KBr discs. 1D- and 2D-NMR Spectra were recorded on a Brucker AVANCE 500 MHz spectrometer in CDCl3 and DMSO-d6. Chemical shifts (δ) are in ppm relative to TMS, multiplicities are shown as follows: s (singlet), d (doublet), t(triplet), m (multiplet) and coupling constants (J) are expressed in hertz (Hz). HRMS was recorded by using a FTICR MS and ESI-TOF-MS Agilent 6230 TOF-MS spectrophotometer (Varian). Progress of the reaction was monitored by thin-layer chromatography (TLC) using precoated TLC sheets with ultraviolet (UV) fluorescent silica gel (Merck 60F254) and spots were visualized by UV lamp at 254 nm. Column chromatography was carried out using silica gel (40-230 mesh). Results: β-Amino alcohols of murrayafoline A (6a-n) were synthesized in 45-67% yields as outlined in Scheme 1 and 3 starting from N-alkylation reaction of murrayafoline A (1) with epichlorohydrin, followed by the opening reaction with different amines using Zinc perchlorate as an effective catalyst. Structure of target compounds was confirmed by NMR and HRMS spectra. The in vitro cytotoxic evaluation was undertaken according to the described protocol. In the present study, murrayafoline A (1) was also evaluated for cytotoxicity against Hep-G2, LU-1, P338 and SW 480 cell lines along with β-amino alcohols (6a-n), and ellipticine was used as positive control for SAR evaluation (Table 1). Although no β-amino alcohols can be compared to the parent compound (murrayafoline A) and ellipticine in terms of IC50 values, some compounds exhibit potential cytotoxic effects against tested cancer cell lines and could be used as important scaffolds in drug development design against human cancer cell lines: Hep-G2, LU-1, P 338 and SW 480 with IC50 values ranging from 3.99-39.89 μg/mL. Conclusion: It is for the first time that thirteen novel β-amino alcohols were synthesized in a simple two-step procedure from murrayafoline A, a carbazole alkaloid isolated from glycosmis stenocarpa in Vietnam. Structures of intermediate and target compounds were elucidated by 1D-, 2D-NMR and HRMS. Evaluation of their cytotoxicity showed that most synthesized β-amino alcohols exhibited activity against four human cancer cell lines: Hep-G2, LU-1, P 338 and SW 480 with IC50 values ranging from 3.99-39.89 μg/mL.Keywords: Murrayafoline A, N-alkylation, opening epoxide, amine, cytotoxicity, cancer.
Graphical Abstract
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