Design, synthesis, and biological evaluation of callophycin A and analogues as potential chemopreventive and anticancer agents

Abstract

Callophycin A was originally isolated from the red algae Callophycus oppositifolius and shown to mediate anticancer and cytotoxic effects. In our collaborative effort to identify potential chemopreventive and anticancer agents with enhanced potency and selectivity, we employed a tetrahydro-β-carboline-based template inspired by callophycin A for production of a chemical library. Utilizing a parallel synthetic approach, 50 various functionalized tetrahydro-β-carboline derivatives were prepared and assessed for activities related to cancer chemoprevention and cancer treatment: induction of quinone reductase 1 (QR1) and inhibition of aromatase, nitric oxide (NO) production, tumor necrosis factor (TNF)-α-induced NFκB activity, and MCF7 breast cancer cell proliferation. Biological results showed that the n-pentyl urea S-isomer 6a was the strongest inducer of QR1 with an induction ratio (IR) value of 4.9 at 50 μM [the concentration to double the activity (CD) = 3.8 μM] and its corresponding R-isomer 6f had an IR value of 4.3 (CD = 0.2 μM). The isobutyl carbamate derivative 3d with R stereochemistry demonstrated the most potent inhibitory activity of NFκB, with the half maximal inhibitory concentration (IC50) value of 4.8 μM, and also showed over 60% inhibition at 50 μM of NO production (IC50 = 2.8 μM). The R-isomer urea derivative 6j, having an appended adamantyl group, exhibited the most potent MCF7 cell proliferation inhibitory activity (IC50 = 14.7 μM). The S-isomer 12a of callophycin A showed the most potent activity in aromatase inhibition (IC50 = 10.5 μM).

A Novel Carboline Derivative Inhibits Nitric Oxide Formation in Macrophages Independent of Effects on Tumor Necrosis Factorαand Interleukin-1βExpression

“…carbolines have been reported to inhibit NO production in macrophages (Lee et al, 2000;Yoon et al, 2005) and other cell types (Newton et al, 2007;Shen et al, 2011;Wong et al, 2011), this biologic activity has typically been associated with suppressed NF-kB activity (Lee et al, 2000;Yoon et al, 2005;Wen et al, 2006;Newton et al, 2007;Shen et al, 2011;Oh et al, 2013) and reduced expression of cytokines and other inflammatory genes transcriptionally regulated by NF-kB (Newton et al, 2007;Oh et al, 2013). A recent screen of 50 functionalized tetrahydro-b-carboline derivatives (Shen et al, 2011) reported that the most potent carboline derivative had IC 50 values for inhibition of NF-kB activity and NO production of 4.8 and 2.8 mM, respectively.…”

“…A recent screen of 50 functionalized tetrahydro-b-carboline derivatives (Shen et al, 2011) reported that the most potent carboline derivative had IC 50 values for inhibition of NF-kB activity and NO production of 4.8 and 2.8 mM, respectively. In comparison, the IC 50 value of 8-Gly carb for inhibition of NO production (∼7 mM) is similar, but the IC 50 value of 8-Gly carb for inhibition of NF-kB activity would exceed 100 mM.…”

“…The 6-chloro-b-carboline derivative ML-102B [N-(6-chloro-7-methoxy-9H-b-carbolin-8-yl)-2-methylnicotinamide] inhibited the production of TNFa and interleukin-2 cytokines in peripheral blood monocytes by blocking NF-kB nuclear translocation (Wen et al, 2006). Biologic screening of 50 functionalized tetrahydro-b-carboline derivatives identified a significant number of these compounds, which decreased NO production coincident with inhibition of NF-kB (Shen et al, 2011). In this study, we investigated the effects of a novel b-carboline derivative, 6-chloro-8-(glycinyl)-aminob-carboline (8-Gly carb), on NO production, NF-kB activation, and cytokine expression in macrophages.…”

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

“…[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-carboline hybrids bearing cinnamoyl or aroyl group at the N2 position, reported in recent literatures, exhibit excellent biological acitivities. 22,23) With these ideas in mind, we conjugated tetrahydro-β-carboline alkaloid with hydroxylcinnamic acid and different nitrogencontaining heterocycle was introduced to positions-N9 of tetrahydro-β-carboline through carbonchain with the purpose for the improvement of water-solubility.…”

“…[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.…”