Short communicationStructure–activity relationships of hybrid annonaceous acetogenins: Powerful growth inhibitory effects of their connecting groups between heterocycle and hydrophobic carbon chain bearing THF ring on human cancer cell lines
Graphical abstract
Highlights
► Five hybrid molecules of annonaceous acetogenins and insecticides were synthesized. ► Growth inhibitory activities against 39 human cancer cell lines were investigated. ► Amide-connected analog showed potent activity against specific cancer cell lines. ► Connecting group between two pharmacophores influenced biological activity.
Introduction
Annonaceous acetogenins are polyketides isolated from Annona plants growing in tropical and subtropical regions [1](b), [1](c), [1], [1](a). They are potent inhibitors of NADH ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport system. Through the inhibition of complex I, ATP production is suppressed particularly in cancer cells that have high metabolic activity, and antitumor activity is initiated. Most acetogenins are white waxy derivatives of long-chain fatty acids (C32 or C34) and the terminal carboxylic acid combines with a 2-propanol unit at the C-2 position to form a methyl-substituted α,β-unsaturated-γ-lactone (Fig. 1). One of their interesting structural features is a single, adjacent, or nonadjacent tetrahydrofuran (THF) or tetrahydropyran system with one or two flanking hydroxyl group(s) at the center of a long hydrocarbon chain. Many total syntheses of natural acetogenins have been reported, motivated by their unique structures and attractive biological activities [2]. The synthesis and evaluation of the biological activities of their analogs were also undertaken by many researchers [3], including our group [4].
Previously, we reported the synthesis of hybrid molecules of annonaceous acetogenins and insecticides targeting mitochondrial complex I because of their biological and structural similarities [5]. Both of these compounds are composed of hydrophobic parts and heterocycles. The derivatives of solamin, a mono-THF acetogenin, which have a nitrogen-containing heterocycle instead of an α,β-unsaturated-γ-lactone, exhibit interesting growth inhibitory activities against human cancer cell lines. One of them, 1-methylpyrazol-5-yl derivative 1, showed selective increase of cytotoxicity to human lung cancer cell lines. In particular, the derivative 1 displayed potent cytotoxicity to NCI-H23, its potency being 80 times higher than that of natural solamin. Then, we shifted our focus to the effects of connecting groups between heterocycles and hydrophobic parts bearing the THF moiety on their biological activities, because the heterocycles of most insecticides are linked to the hydrophobic parts with an amide group. As a result of preliminary examinations, amide-connected hybrid acetogenin 2 was found to possess very potent growth inhibitory activity against human cancer cell lines. In this letter, we report the synthesis and biological evaluation of a new series of hybrid annonaceous acetogenins whose heterocyclic parts are connected to hydrophobic parts by an amide bond or its equivalent.
Section snippets
Results and discussion
Scheme 1 shows the synthesis of amide-connected hybrid acetogenin 2. The asymmetric alkynylation of aldehyde 7, which was stereoselectively synthesized by our method [6], [7], with 10-azido-1-decyne 8 under Carreira's conditions [8], and with (1R,2S)-N-methylephedrine as the chiral ligand afforded propargyl alcohol 9 in 84% yield with high stereoselectivity [9]. Simultaneous reduction of the triple bond and the azide with Pearlman's catalyst in THF afforded primary amine 10 in good yield.
Conclusion
In summary, five novel hybrid annonaceous acetogenins were synthesized and their growth inhibitory activities against 39 human cancer cell lines were investigated. It was revealed that the connecting group between the N-methylpyrazole part and the hydrophobic alkyl chain bearing the THF ring influenced their biological activities very powerfully. In particular, amide-connected analog 2 showed selective and very potent activity (<10 nM) against some cancer cell lines. These data indicate the
Chemistry
Melting points are uncorrected. Optical rotations were measured by using a JASCO DIP-360 digital polarimeter or a JASCO P-1020 digital polarimeter. 1H NMR spectra were recorded in the specified solvent with a JEOL JNM-GX-500 spectrometer (500 MHz) or a JEOL JNM-EX-270 spectrometer (270 MHz). 13C NMR spectra were recorded in the specified solvent with a JEOL JNM-AL300 spectrometer (75 MHz), a JEOL JNM-ECS-400 spectrometer (100 MHz) or a JEOL JNM-GX-500 spectrometer (125 MHz). Chemical shifts are
Acknowledgments
In vitro antiproliferative activities of hybrid annonaceous acetogenins against human cancer cell lines were examined by the Screening Committee of New Anticancer Agents supported by a Grant-in-Aid for Scientific Research on Priority Area ‘Cancer’ from The Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT). This work was supported in part by Grants-in-Aid for Young Scientists (B) [Nos. 21790113, 23790130], a Grant-in-Aid for Scientific Research (B) [No. 22390021] from
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2015, Bioorganic and Medicinal ChemistryCitation Excerpt :The molar concentration of a test compound required for 50% growth inhibition (GI50) of cells was calculated as reported previously. A detailed method is described elsewhere.14 COMPARE analysis was performed by calculating the Pearson correlation coefficient (r) between the GI50 mean graphs of compounds X and Y using the following formula: r = ((xi − xm) (yi − ym))/((xi − xm)2 (yi − ym)2)1/2, where xi and yi are Log GI50 of the two compounds, respectively, for each cell line, and xm and ym are the mean values of xi and yi, respectively (n = 39).