Synthesis and bioactivity assay of Tetrahydro-beta-Carboline and Beta-Carboline derivatives and Extraction of bioactive compounds from plant for medical purposes

Abstract

Tetrahydro-beta-carboline (THβC) and beta-carboline (βC) derivatives are one of indole scaffolds and are widely found in natural products such as plants, fungi and marines. Many of these compounds display various biological and pharmacological activities such as inhibit the monoamine oxidase (MAO-A), antioxidant, anticancer, and antifungal activities. Moreover, the structure-activity relationship (SAR) studies indicated that THßC derivatives with substitutions with aromatic ring at 1-position and also ester at 3-position would make great influence on their biological activities. Thus, the synthesis of THßCs derivatives bearing the substituted at C-1 and C-3 was of interest and Pictet-Spengler reaction was used as a key step to evaluate for their biological activities. In first plan, the synthesis was started from tryptamine or L-tryptophan methyl ester with various aldehydes via Pictet-Spengler to provide 1-substituted THßCs and diastereomeric mixture of 1,3-disubstituted THßCs, respectively. The obtained THβCs were oxidized with sulfur powder under ambient oxygen to afford the C1 and/or C3 substituted ßCs. All the synthesized compounds were confirmed by NMR analysis. Moreover, all compounds were investigated for in vitro cytotoxicity against human cancer cell lines by MTT assay and antioxidant activity by DPPH radical-scavenging assay. Doxorubicin, acridine orange and trolox were used as a standard drug for cytotoxicity and antioxidant activity, respectively. However, all synthesized compounds showed potency less than that of the standard drug both in cytotoxicity and antioxidant activity.

And in second plan, in continuous study for investigation of the influence of configuration at C-1 position on their biological activities, 1-substituted THβC derivatives were reported in enantioselective synthesis. At first, we attempted to construct of piperidine ring via asymmetric Pictet-Spengler by using Boc-protected proline and N,N-phthaloyl-protected amino acid chloride as chiral auxiliary and Titanium isopropoxide as catalyst but this synthetic strategy was not successful regarding to the steric repulsion between chiral auxiliary and substituent of the parent compound. Then, the synthetic strategy of enantioselective synthesis of 1-substituted THßCs was designed via asymmetric Pictet-Spengler with cocatalyzed by a chiral thiourea and benzoic acid. Moreover, we attempted to SAR study of substituted methyl ester at C-3 compared the parents by chromatographic separation of cis/trans 1,3-disubstituted THßCs to pure trans 1,3-disubstituted THßCs. Their structures were elucidated by 1H, 13C NMR and 1H-1H NOESY spectroscopic analyses. Later on, all of enantioselective 1-substituted THßCs and trans 1,3-disubstituted THßCs have been investigated their biological activities compared to the mixture compounds in first plan.

Moreover, the isolation of Cannabinoids led to study the bioassay of Cannabis indica. Their isolated structures were elucidated by spectroscopic analysis and compared with previous literatures. All compounds were conducted to explore cytotoxic activities using MTT assay. In particular, CBD was found to exhibit the most promising cytotoxic effect against MDA-MB-231 cell with the lowest IC50 value of 4.14 µg/mL.

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