Synthetic optimization of ellipticine and antitumor activity of novel hexacyclic derivatives of ellipticine.

A high-yield synthetic procedure of ellipticine has been optimized, and the total yield was up to 50% without silica gel column chromatography. Novel hexacyclic ellipticine derivatives were synthesized by coupling ellipticine with o-aminobenzoic acid. Their cytotoxicities against HCT116, MGC803, HT29 and MCF-7 tumor cells were evaluated. Compound 1a, 1k, 1l showed cytotoxic activity comparable to that of ellipticine. The study of in vivo antitumor activity showed the derivative 1l possessed significant growth inhibitory effect against two types of mouse tumor models and one a human lung cancer xenograft model. The anti-tumor effect of compound 1l was better than that of ellipticine, and could arrest cell cycle at the G2 phase and induced late apoptosis in lung cancer cells analyzed by FCM. The study of mechanism of action suggested that 1l might be a topoisomerase IIα inhibitor.

[1]  R. Diana,et al.  Evaluating the biological properties of synthetic 4-nitrophenyl functionalized benzofuran derivatives with telomeric DNA binding and antiproliferative activities. , 2019, International journal of biological macromolecules.

[2]  E. Bonmassar,et al.  Antitumour activity of resveratrol on human melanoma cells: A possible mechanism related to its interaction with malignant cell telomerase. , 2017, Biochimica et biophysica acta. General subjects.

[3]  V. Roviello,et al.  Lac-l-TTA, a novel lactose-based amino acid–sugar conjugate for anti-metastatic applications , 2017, Amino Acids.

[4]  V. Roviello,et al.  Benzodifuran Derivatives as Potential Antiproliferative Agents: Possible Correlation between Their Bioactivity and Aggregation Properties. , 2017, ChemPlusChem.

[5]  Tengfei Ji,et al.  Synthesis and antitumor activity of novel substituted uracil-1'(N)-acetic acid ester derivatives of 20(S)-camptothecins. , 2017, European journal of medicinal chemistry.

[6]  V. Roviello,et al.  Synthesis and biological evaluation of a novel Amadori compound , 2017, Amino Acids.

[7]  Ali Hassanali,et al.  Nuclear quantum effects in a HIV/cancer inhibitor: The case of ellipticine. , 2016, The Journal of chemical physics.

[8]  M. Zhang,et al.  Condensation of anthranilic acids with pyridines to furnish pyridoquinazolones via pyridine dearomatization. , 2016, Chemical communications.

[9]  Sevil Zencir,et al.  Inhibition of human DNA topoisomerase IIα by two novel ellipticine derivatives. , 2016, Bioorganic & medicinal chemistry letters.

[10]  R. Sreenivasulu,et al.  Synthesis and biological evaluation of benzimidazole fused ellipticine derivatives as anticancer agents , 2016, Monatshefte für Chemie - Chemical Monthly.

[11]  F. Zsila.  The anticancer agent ellipticine binds to glycosaminoglycans at mildly acidic pH characteristic of the extracellular matrix of tumor tissues , 2016 .

[12]  T. Cotter,et al.  7-formyl-10-methylisoellipticine, a novel ellipticine derivative, induces mitochondrial reactive oxygen species (ROS) and shows anti-leukaemic activity in mice , 2016, Investigational New Drugs.

[13]  A. Banerjee,et al.  Recognition of chromatin by the plant alkaloid, ellipticine as a dual binder. , 2015, Biochemical and biophysical research communications.

[14]  Mamta Baunthiyal,et al.  Computer aided screening of natural compounds targeting the E6 protein of HPV using molecular docking , 2015, Bioinformation.

[15]  Charlotte M. Miller,et al.  Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells , 2014, Investigational New Drugs.

[16]  A. Maguire,et al.  Synthesis and evaluation of novel ellipticines as potential anti-cancer agents. , 2013, Organic & biomolecular chemistry.

[17]  H. Knölker,et al.  Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids. , 2012, Chemical reviews.

[18]  A. Samanta,et al.  Dual fluorescence of ellipticine: excited state proton transfer from solvent versus solvent mediated intramolecular proton transfer. , 2012, The journal of physical chemistry. A.

[19]  Jieun Park,et al.  Ellipticine induces apoptosis in human endometrial cancer cells: the potential involvement of reactive oxygen species and mitogen-activated protein kinases. , 2011, Toxicology.

[20]  J. Hudeček,et al.  Cytochrome b(5) shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy. , 2011, Biochemical pharmacology.

[21]  C. Nguyen,et al.  Antitumor activity of pyridocarbazole and benzopyridoindole derivatives that inhibit protein kinase CK2. , 2010, Cancer research.

[22]  J. Duhamel,et al.  Solvent effect on the photophysical properties of the anticancer agent ellipticine. , 2006, The journal of physical chemistry. A.

[23]  K. Kohn,et al.  Apoptosis induced by topoisomerase inhibitors. , 2003, Current medicinal chemistry. Anti-cancer agents.

[24]  H. Knölker,et al.  Isolation and synthesis of biologically active carbazole alkaloids. , 2002, Chemical reviews.

[25]  J F Barrett,et al.  Design, synthesis, and biological evaluation of ellipticine-estradiol conjugates. , 1996, Journal of medicinal chemistry.

[26]  G. Gribble.  Chapter 7 Synthesis and Antitumor Activity of Ellipticine Alkaloids and Related Compounds , 1990 .

[27]  T. Honda,et al.  Synthesis and antitumor activity of quaternary ellipticine glycosides, a series of novel and highly active antitumor agents. , 1988, Journal of medicinal chemistry.

[28]  C. Auclair.  Multimodal action of antitumor agents on DNA: the ellipticine series. , 1987, Archives of biochemistry and biophysics.

[29]  Lk Dalton,et al.  Synthesis of the tumour-inhibitory alkaloids, ellipticine, 9-methoxyellipticine, and related pyrido[4,3-b]carbazoles , 1967 .