OBJECTIVE To explore the efficient and economical synthesis method of asymmetric monocarbonyl curcumin analogues(AMCACs), design and sgnthesize a series of B19(1E,4E)-1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one analogs to investigate their anti-gastric cancer activities in vitro.METHODS A series of asymmetric B19 analogues containing 2,3-dimethoxyphenyl were designed via the combination principle of medicinal chemistry, and obtained a method for synthesizing intermediate (E)-2-(2,3- dimethoxybenzylidene)cyclopentanone by one step catalyzed by L-proline. The targeted compounds were screened by MTT assay, and colony cloning experiments were used to further verify its anti-gastric cancer activity in vitro.RESULTS Ten novel target compounds were synthesized, and the structures were confirmed by LC-MS and 1H-NMR spectral analysis. Among them, compound 6e had the highest inhibitory activity on the growth of gastric cancer cells SGC-7901 and BGC-823, whose IC50 were 9.80 and 13.50 μmol·L-1, respectively.CONCLUSIONL-proline could be used as a catalyst to synthesize asymmetric monocarbonyl curcumin analogues efficiently and economically. Compound 6e could effectively inhibit the growth of gastric cancer cells in vitro, and its toxicity and inhibition mechanism of tumor cell growth need to be further studied.
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CHENG Jia-mei, WANG Pei-hua, ZHU-Min, ZHAO-Min, WU Jian-zhang, WANG Jia-bing. Synthesis of (1E,4E)-1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one Analogs and Its Anti-gastric Cancer Activity In Vitro. Chinese Pharmaceutical Journal, 2018, 53(23): 1978-1983.
NELSON K M, DAHLIN J L, BISSON J, et al. The essential medicinal chemistry of curcumin. J Med Chem, 2017, 60(5):1620-1637.
[2]
WU J Z, CHEN X, WANG X Q, et al. Studies on synthesis and antitumor activity of a curcumin-selenium compound. Chin Pharm J (�й�ҩѧ��־),2009, 44(23):1830-1832.
[3]
BIMONTE S, BARBIERI A, PALMA G, et al. Curcumin inhibits tumor growth and angiogenesis in an orthotopic mouse model of human pancreatic cancer. Bio Med Res, 2013, 2013(6):810423.
[4]
GORDON O N, LUIS P B, SINTIM H O, et al. Unraveling curcumin degradation: autoxidation proceeds through spiroepoxide and vinylether intermediates enroute to the main bicyclopentadione. J Biol Chem, 2015, 290(8):4817-4828.
[5]
PATWARDHAN R S, CHECKER R, SHARMA D, et al. Dimethoxycurcumin, a metabolically stable analogue of curcumin, exhibits anti-inflammatory activities in murine and human lymphocytes. Biochem Pharmacol, 2011, 82(6):642-657.
[6]
CHAKRABORTI S, DHAR G, DWIVEDI V, et al. Stable and potent analogues derived from the modification of the dicarbonyl moiety of curcumin . Biochemistry, 2013, 52(42):7449-7460.
[7]
WANG Y, XIAO J, ZHOU H P, et al. A novel monocarbonyl analogue of curcumin, (1E,4E)-1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one, induced cancer cell H460 apoptosis via activation of endoplasmic reticulcum stress signaling pathway. J Med Chem, 2011, 54(11):3768-3778.
[8]
WENG Q Y, FU L L, CHEN G Z,et al. Design, synthesis, and anticancer evaluation of long-chain alkoxylated mono-carbonyl analogues of curcumin. Eur J Med Chem, 2015, 103:44-55.
[9]
SHAO W Y, GAO Y N, YU Z W, et al. Facile preparation of new unsymmetrical curcumin derivatives by solid-phase synthesis strategy. Tetrahedron Lett, 2006, 47(24):4085-4089.
[10]
SHI W, DOLAI S, RIZK S, et al. Synthesis of monofunctional curcumin derivatives, clicked curcumin dimer, and a PAMAM dendrimer curcumin conjugate for therapeutic applications. Org Lett, 2007, 9(26):5461-5464.
[11]
WU J Z, REN J Y, YAO S, et al. Novel antioxidants�� synthesis and their anti-oxidative activity through activating Nrf2 signaling pathway. Bioorg Med Chem Lett, 2017, 27(7):1616-1619.
[12]
WANG Z, ZOU P, LI C L, et al. Synthesis and biological evaluation of novel semi-conservative monocarbonyl analogs of curcumin as anti-inflammatory agents. Med Chem Commun, 2015, 6(7):1328-1339.
[13]
MOHD ALUWI M F F, RULLAH K, YAMIN B M, et al. Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E production in LPS-induced murine and human macrophages cell lines. Bioorg Med Chem Lett, 2016, 26(10):2531-2538.
[14]
YANG S D, WU L Y, YAN Z Y, et al. A novel ionic liquid supported organocatalyst of pyrrolidine amide: synthesis and catalyzed Claisen-Schmidt reaction. J Mol Catal A Chem, 2007, 268(1-2):107-111.
[15]
QIAN H, LIU D B. Synthesis of chalcones via Claisen-Schmidt reaction catalyzed by sulfonic acid-functional ionic liquids. Ind Eng Chem Res, 2011, 50(2):1146-1149.
[16]
CHOUDARY B M, KANTAM M L, RANGANATH K V S, et al. Bifunctional nanocrystalline MgO for chiral epoxy ketones via Claisen-Schmidt condensation-asymmetric epoxidation reactions. J Am Chem Soc, 2014, 126(11):3396-3397.
[17]
HO P E, TAO J, MURPHY G K. Wittig reagents as metallocarbene precursors: in situ generated monocarbonyl iodonium ylides. Eur J Org Chem, 2013, 2013(29):6540-6544.
[18]
LIN A J, WANG J Y, MAO H B, et al. Organocatalytic asymmetric Michael-type/Wittig reaction of phosphorus ylides: synthesis of chiral alpha-methylene-delta-ketoesters. Org Lett, 2011, 13(16):4176-4179.
[19]
DU Z Y, BAO Y D, LIU Z, et al. Curcumin analogs as potent aldose reductase inhibitors. Arch Pharm Chem Life Sci, 2016,339(3):123-138.
[20]
OHORI H, YAMAKOSHI H, TOMIZAWA M, et al. Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer. Mol Cancer Ther, 2006, 5(10):2563-2571.
[21]
ZHAO C G, CAI Y P, HE X Z, et al. Synthesis and anti-inflammatory evaluation of novel mono-carbonyl analogues of curcumin in LPS-stimulated RAW 264.7 macrophages. Eur J Med Chem, 2010, 45(12):5773-5780.
[22]
QIU P H, ZHANG S S, ZHOU Y Y, et al. Synthesis and evaluation of asymmetric curcuminoid analogs as potential anticancer agents that downregulate NF-kB activation and enhance the sensitivity of gastric cancer cell lines to irinotecan chemotherapy. Eur J Med Chem, 2017, 139:917-925.
[23]
JIN R, XIA Y Q, CHEN Q X, et al. Da0324, an inhibitor of nuclear factor-��Bactivation,demonstrates selective antitumor activity on human gastric cancer cells. Drug Des Dev Ther, 2016, 10:979-995.
2018, Vol. 53 
