棉酚肉桂酸酯的合成及抗白血病活性研究
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摘要
棉酚8,8′-CHO是棉酚主要的毒性基团,棉酚醛基互变异构后,双醇酮式可与肉桂酸成酯,生成新的化合物细胞毒性作用减小,同时获得新的棉酚母核先导化合物.以棉酚与肉桂酸为原料,合成了未见报道的棉酚肉桂酸酯.通过~1H-NMR、~(13)C-NMR对合成的化合物进行了结构表征,并应用HL-60、Jurkat和K562这3种人类白血病细胞系,采用CCK-8法评价棉酚肉桂酸的体外抗白血病活性.CCK-8实验结果显示,棉酚肉桂酸酯对Jurkat细胞具有较强的抑制活性.棉酚双醇酮式能与肉桂酸反应生成新化合物棉酚肉桂酸酯,新化合物的细胞毒性作用减小,同时抗白血病活性较强,为进一步的药物设计与临床前研究提供了相应的理论和实验依据,为棉酚结构衍生化提供了新思路和新途径.
Gossypol 8,8′-CHO is the main toxic group of gossypol.After the esterification of gossypol and cinnamic acid,the aldehyde group of gossypol is replaced by a newly formed ester group,and the cytotoxicity of the new compound is reduced.A new compound with better activity is obtained.An unreported gossypol cinnamate was synthesized from gossypol and cinnamic acid.The synthesized compounds were characterized by ~1H-NMR,~(13)C-NMR and MS,and the human antitumor activities of gossypol cinnamic acid were evaluated by CCK8 method using three human leukemia cell lines,HL-60,Jurkat and K562.A new compound of gossypol cinnamate was obtained by synthetic experiments.Gossypol cinnamate has significant inhibitory activity against Jurkat.The new compound,gossypol cinnamate,which is a reaction of gossypol diol ketone with cinnamic acid,provides a new way of thinking and new ways to derivatize gossypol structure.The cytotoxicity of the new compounds is reduced,while increasing its biological activity,providing a basis for further drug design and preclinical research.
Gossypol 8,8′-CHO is the main toxic group of gossypol.After the esterification of gossypol and cinnamic acid,the aldehyde group of gossypol is replaced by a newly formed ester group,and the cytotoxicity of the new compound is reduced.A new compound with better activity is obtained.An unreported gossypol cinnamate was synthesized from gossypol and cinnamic acid.The synthesized compounds were characterized by ~1H-NMR,~(13)C-NMR and MS,and the human antitumor activities of gossypol cinnamic acid were evaluated by CCK8 method using three human leukemia cell lines,HL-60,Jurkat and K562.A new compound of gossypol cinnamate was obtained by synthetic experiments.Gossypol cinnamate has significant inhibitory activity against Jurkat.The new compound,gossypol cinnamate,which is a reaction of gossypol diol ketone with cinnamic acid,provides a new way of thinking and new ways to derivatize gossypol structure.The cytotoxicity of the new compounds is reduced,while increasing its biological activity,providing a basis for further drug design and preclinical research.
引文
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[2] Liu J,Benedict C R,Stipanovic R D,et al.Purification and characterization of S-adenosyl-L-methionine:DesoxyhemI gossypol-6-O-methyltransferase from cotton plants an enzyme capable of methylating the defense terpenoids of cotton[J].Plant Physiology,1999,121(3):1 017-1 024.
[3] Marchlewski,L.Gossypol,ein Bestand-theil der baumwoll- samen[J].Journal for Prak-tische Chemie,1899,60(1):84-90.
[4] Sonenberg M,Huang J T,Ren Y F,et al.Anti-fertility and other actions of gossypol analogues[J].Contraception,1988,37(3):247-255.
[5] Radloff R J,Deck L M,Royer R E,et al.Antiviral activities of gossypol and its derivatives against herpes simplex virus type II[J].Pharmacol Res Commun,1986,18(11):1 063-1 073.
[6] Lin T S,Schinazi R,Griffith B P,et al.Selective inhibition of human immunodeficiency virus type 1 replication by the (-) but not the (+) enantiomer of gossypol[J].Antimicrobial Agents & Chemotherapy,1989,33(12):2 149-2 151.
[7] Schwartze E W,Alsberg C L .Relation between toxicity of cotton-seed and its gossypol content[J].Journal of the Franklin Institute,1924,198(5):709-709.
[8] Royer R E,Deck L M,Vander Jagt T J,et al.Synthesis and anti-HIV activity of 1,1′-dideoxygossypol and related compounds[J].Journal of Medicinal Chemistry,1995,38(13):2 427-2 432.
[9] Vander Jagt D,Deck L,Royer R.Gossypol prototype of inhibitors targeted to dinucleotide folds[J].Current Medicinal Chemistry,2000,7(4):479-498.
[10] Freedman T B,Cao X,Oliveira R V,et al.Determination of the absolute configuration and solution conformation of gossypol by vibrational circular dichroism[J].Chirality,2003,15(2):196-200.
[11] Yang J,Li L L,Li J R,et al.Synthesis and biological evaluation of water-soluble derivatives of chiral gossypol as HIV fusion inhibitors targeting gp41[J].Bioorganic & Medicinal Chemistry Letters,2017,28(1):49-52.
[12] Chenjiang H,Ho C T.Antioxidant activities of caffeic acid and its related hydroxycinnamic acid compounds[J].J.agric.food Chem,1997,45(7):2 374-2 378.
[13] Manley P W,Cowan Jacob S W,Buchdunger E,et al.Imatinib:A selective tyrosine kinase inhibitor[J].European Journal of Cancer,2002,38(supp-S5):19-27.
[14] Dohse M,Scharenberg C,Shukla S,et al.Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib,nilotinib,and dasatinib[J].Drug Metabolism and Disposition,2010,38(8):1 371-1 380.
[15] Haberler C,Gelpi E,Marosi C,et al.Immunohistochemical analysis of platelet-derived growth factor receptor-α,-β,c-kit,c-abl,and arg proteins in glioblastoma:Possible implications for patient selection for imatinib mesylate therapy[J].Journal of Neuro-Oncology,2006,76(2):105-109.
[16] Mukherjee J,Kamnasaran D,Balasubramaniam A,et al.Human schwannomas express activated platelet-derived growth factor receptors and c-kit and are growth inhibited by gleevec (imatinib mesylate)[J].Cancer Research,2009,69(12):5 099-5 107.
[17] Moawad E Y.Predicting effectiveness of imatinib mesylate in tumors expressing platelet-derived growth factors (PDGF-AA,PDGF-BB),stem cell factor ligands and their respective receptors (PDGFR-α,PDGFR-β,and c-kit)[J].Journal of Gastrointestinal Cancer,2015,46(3):272-283.
[18] Oliver C L,Miranda M B,Shangary S,et al.(-)-Gossypol acts directly on the mitochondria to overcome Bcl-2- and Bcl-X(L)-mediated apoptosis resistance[J].Molecular Cancer Therapeutics,2005,4(1):23-31.
[19] Soderquist R,Bates D J,Danilov A V,et al.Gossypol overcomes stroma-mediated resistance to the BCL2 inhibitor ABT-737 in chronic lymphocytic leukemia cells ex vivo[J].Leukemia,2013,27(11):2 262-2 264.
[20] Wong F Y,Liem N,Xie C,et al.Combination therapy with gossypol reveals synergism against gemcitabine resistance in cancer cells with High BCL-2 expression[J].Plos One,2012,7(12):e50 786.