目的 设计、合成desmosdumotin-C的B环修饰衍生物,并考察其体外抗肿瘤活性。方法 以2,4,6-三羟基苯乙酮为起始原料,经苯环烷基化、4-O-烷基化2步反应制得多烷基取代的A环;以对醛基苯甲酸为原料,经Schotten-Baumannn反应制得含有氨基酸酰胺结构的B环;最后通过Claisen-Schmidt反应连接A环和B环或芳醛制得目标化合物。通过磺基罗丹明B法对所合成的目标化合物进行体外肿瘤细胞增殖抑制活性评价。结果 制备合成了17个目标化合物,其中12个为新化合物,其结构经MS,1H-NMR确证;目标化合物体外抗肿瘤活性表明,大部分化合物的活性优于或相当于desmosdumotin-C。结论 通过对先导物desmosdumotin-C进行结构修饰和改造可有效提高化合物的抗肿瘤活性,如在A环引入长烷基链,在B环引入卤素、氨基酸酰胺结构等,为后续desmosdumotin-C衍生物的结构优化提供方向和数据支持。
Abstract
OBJECTIVE To design and synthesize desmosdumotin C derivatives on B-ring and investigate their antitumor activities in vitro. METHODS The A-ring of the target compounds was firstly synthesized from 2,4,6-trihydroxyacetophenone by alkylation and 4-O-alkylation. Then the B-ring was synthesized by the Schotten-Baumannn reaction. Finally, the derivatives of desmosdumotin C with amide-linked substituents or aromatic aldehydes on B-ring were synthesized by the Claisen-Schmidt reaction. The antitumor activities of the compounds were evaluated by SRB assay. RESULTS Seventeen target compounds were synthesized, 12 of which were new compounds. All of them were confirmed by 1H-NMR and MS spectra. Preliminary pharmacological test showed that most of the compounds had equal or better antitumor activities than desmosdumotin C in vitro. CONCLUSION The structural modifications of desmosdumotin C would significantly increase the antitumor activity of the compounds, such as long alkyl chain substituted Ring A, amino acid amides on B-ring and so on, which provides the basis for the structure optimization of desmosdumotin C derivatives.
关键词
Desmosdumotin-C /
衍生物 /
氨基酸酰胺修饰 /
合成 /
抗肿瘤
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Key words
desmosdumotin C /
derivatives /
amino acid amides modification /
synthesis /
antitumor
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中图分类号：
R914
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参考文献
[1] WU J H, MCPHAIL A T, BASTOW K F, et al. Desmosdumotin C, a novel cytotoxic principle from Desmos dumosus. Tetrahedron Lett, 2002, 43(8):1391-1393.[2] KYOKO N G, WU J H, KENNETH F, et al. Antitumor agents 243. Syntheses and cytotoxicity of desmosdumotin C derivatives . Bioorg Med Chem, 2005, 13(6):2325-2330.[3] KYOKO N G, CHEN T H, PENG C Y, et al. Antitumor agents 259. Design, syntheses, and structure-activity relationship study of desmosdumotin C analogs. J Med Chem, 2007, 50(14):3354-3358.[4] KYOKO N G, WU P C, BASTOW K F, et al. Antitumor agents 283. Further elaboration of desmosdumotin C analogs as potent antitumor agents:Activation of spindle assembly checkpoint as possible mode of action. Bioorg Med Chem, 2011, 19(5):1816-1822.[5] LI E Z, SONG M Y, XING Z, et al. Synthesis and antitumor evaluation of desmosdumotin C derivatives on B-ring . Chin Pham J(中国药学杂志), 2013, 48(11):924-929. [6] NUSHMIA Z K, YUHONG S, VALERIE W R, et al. Experimental therapeutics, preclinical pharmacology experimental therapeutics with a new 10-deazaaminopterin in human mesothelioma:Further improving efficacy through structural design, pharmacologic modulation at the Level of MRP ATPases, and combined therapy with Platinums. Clin Cancer Res, 2001, 7(10):3199-3205.[7] KYOKO N G, WU J H, LEE K H. First total synthesis of desmosdumotin C. Synth Commun, 2005, 35(13):1735-1739. HU C M. Studies on designation and synthesis of the leading compound desmosdumotin C derivatives. Beijing:Academy of Military Medical Sciences, 2007. [8] HUANG D M, SHEN Y C, WU C, et al. Investigation of extrinsic and intrinsic apoptosis pathways of new clerodane diterpenoids in human prostate cancer PC-3 cells . Euro J Pharm, 2004, 503(1-3):17-24.
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脚注
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基金
国家自然科学基金资助课题(81072546;81470156)
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