Synthesis and <i>in Vitro</i> Biological Evaluation of Hybrids from Tetrahydro-β-carboline and Hydroxylcinnamic Acid as Antitumor Carcinoma Agents

Abstract

Novel hybrids 8a-j and 9a-j were designed and synthesized by coupling the carboxyl group of hydroxylcinnamic acids with tetrahydro-β-carboline alkaloids which were linked with different substituted nitrogen-containing heterocycles at the positions-N9, and their in vitro biological activities were evaluated. It was found that most hybrids showed good to moderate anti-tumor activities. Especially, compound 9j had a great potency superior to 5-fluorouracil (5-FU) and comparable to adriamycin in human cancer cells, and could selectively inhibit tumor cells, but not inhibit non-tumor cell proliferation in vitro. More importantly, apoptosis assay indicated that 9j could significantly induce tumor cell apoptosis in a dose-dependent manner. Therefore, our novel findings may provide a new framework for the design of new hybrids for the intervention of human cancers.Key words synthesis; tetrahydro-β-carboline; hydroxylcinnamic acid; anti-tumor agent; inhibitory activity; cell apoptosisCancer is a major health problem worldwide and is the leading cause of human mortality exceeded only by cardiovascular diseases.1) Therefore, development of new anticancer drugs and more effective treatment strategies for cancer are of utmost importance when traditionally prescribed chemotherapeutic agents have problems with toxicity and drug resistance.2)The tetrahydro-β-carboline alkaloids, a large group of synthetic and naturally occurring polycyclic indolic compounds, have attracted a great deal of interest amongst medicinal chemists and pharmacologists over the years, partially due to their widespread potent biological and pharmaceutical properties including antimalarial, antitumor, anti-human immunodeficiency virus (HIV), anti-thrombotic, and antimicrobial activities. [3][4][5][6][7][8] Recently, more attention has been focused on the study of the tetrahydro-β-carboline derivatives about their potential antitumor activities. 4,5,9,10) Current issues in cancer research show that many tricyclic ring carboline compounds which display potent cytotoxicity against numerous cancer cell lines are harman and norharman derivatives, 11) and more complex structures such as manzanine, 12) azatoxin, 13) eudistomine K, 14) fascaplysine, 15) and picrasidine L. 16) Therefore, the structural fragment of tetrahydro-β-carboline seems to be essential for many biologically important indole alkaloids and represents an important lead structure for the development of novel anticancer agents.In an ongoing study on discovering new anti-tumor agents for human use, we were inspired by the fact that hydroxylcinnamic acids, such as ferulic acid and p-hydroxy-cinnamic acid, are known as phenolic compounds occurring in natural plant product, and their derivatives displayed selective antiproliferative activity against some types of cancer cells, [17][18][19] which attracts considerable attention from medicinal chemists.There is an increased interest in the use of hybrid molecules for drug discovery against a multitude of disease indications.20,21) Many tetrahydro-β-car...

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