Dissertation > Excellent graduate degree dissertation topics show

Design, Synthesis and Biological Evaluation of Novel Podophyllotoxin Derivatives as Antitumor Agents

Author: WangLi
Tutor: HuYongZhou
School: Zhejiang University
Course: Pharmacy
Keywords: podophyllotoxin etoposide cytotoxicity antitumor activity anti-drug-resistance structure-activity relationship
CLC: R284
Type: Master's thesis
Year: 2011
Downloads: 15
Quote: 0
Read: Download Dissertation

Abstract


Podophyllotoxin (PDT), a kind of aryltetralin lignans, shows multiple biological effects such as anti-fungal, anti-tumor, anti-virus, anti-insect activities. Etoposide (VP-16) and teniposide (VM-26) are two semi-synthetic derivatives of podophyllotoxin, which have been officially approved for clinical use against various types of cancers including breast cancer, testicular cancer, non small-cell lung cancer, lymphoma and childhood leukemia. However, VP-16 and VM-26 exhibit several toxic side effects, acquired drug-resistance and poor water-solubility, which block their further application. Therefore, it remains a hotspot for medicinal chemists to develop novel anticancer agents with high efficacy and-low toxicity.In previous studies, we reported a series of C-4β-N-substituted podophyllotoxin derivatives. Further biological evaluation showed that C-4β-anilino derivatives were effective in the treatment of cancer in drug-sensitive and drug-resistant xenograft models. Based on the structural features of the above-mentioned compounds, rational drug design principle were utilized and 44 novel 4β-susbtitued anilino-4’-O-demethyl-4-desoxypodophyllotoxin (series E, GL and O) were designed, synthesized, and confirmed by IR,1H NMR, 13C NMR and MS. In vitro cytotoxicities were tested against four human tumor cell lines, and most compounds showed improved activities against 95D and KB/VCR when compared to VP-16. The inhibitory rate of GL-3 on Sarcoma S180 in mice was 58.1%, which is higher than that of positive control cisplatin (45.8%). GL-3 could significantly inhibit the tumor growth (57.3%) on highly metastatic human lung cancer xenograft in nude mice. It is worthy to make further research about this compound to be a novel anticancer agent.Based on the extremely significant role that the disulfide bond played in the natural antitumor agents, we introduced this important moiety as a substituent to 4 position of podophyllotoxin.8 novel 4’-O-demethyl-4-desoxypodophyllotoxin derivatives containing disulfide side chain were designed, synthesized, and confirmed by 1H NMR and MS. Most compounds exhibited moderate or more potent cytotoxic activities than that of VP-16, especially the cytotoxicities against human leukemia cell line K562 with 2.5-38 folds more potent than that of VP-16. Besides, most of the compounds showed better anti-drug-resistant activities than that of VP-16.

Related Dissertations

  1. Screening of anti-tumor activity of curcumin derivatives and U87 cells,R285.5
  2. Preliminary Study on the Antitumor Activities of the Natural Products D5, S3 and Their Derivatives,R285.5
  3. Studies on Structure and Properties of Biopolymer Composite Materials Based on Carbon Nanotubes,TB383.1
  4. Organotin compounds containing the N atom of carboxylic acid - based synthesis , structural characterization and properties of,O627.42
  5. Studies on Seed Dormancy Characteristics and Its Embryo Tissue Culture of Podophyllum Hexandrum Royle,S567.239
  6. The Polyphasic Taxonomy and Antitumor Activity Analysis of Actinomycetes Isolated from KaLa Mountains in Tibet,Q93
  7. The Study on the Antitumor Activity of the Immunosuppressive Agent FTY720 to the Rat Hepatocellular Transplanted Tumor,R735.7
  8. Anti-MDR Tumor Cells Activities of ZM-16 and Its Mechanism of Action,R730.5
  9. The Mechanisms of Paclitaxel and the Effect of Paclitaxel-based Multidrug Combinations on Inhibiting SKOV3 Ovarian Cancer Cells,R737.31
  10. Studies of Phenylallyl Compounds of Guizhi-Tang on Structure-activity Relationship and PGE2 Release with TRPV4 Expression,R289
  11. Research on the Key Synthetic Intermediate of Podophyllotoxin,TQ463
  12. Screening on 171 Natural Natural Products for Proteasomes Inhibitive Activity,R965.1
  13. Experimental Study on Antileukemia Effect of 5-methyl Sulfafurazole Schiff’s Sodium,R733.7
  14. Preparation and the Structure-Activity-Relationship Study of Sulfated Salvia Polysaccharide,R285
  15. Enhancement of Branched Polyethylenimine (BPEI)-Mediated Gene Transfection Efficiency by a Hydrophobic Peptide from Melittin and Its Application in siRNA Transfection,R346
  16. Synthesis and Application of Novel Cationic Copolymers as Nonviral Gene Vectors,R346
  17. Synthesis, Activity and Fluorescence Imaging of Novel Monofunctional Antitumor Platinum Complexes,O627.8
  18. QSAR Studies on Reaction Rate Constants of Selected Organic Pollutants with·OH,X13
  19. Controllable Hydrolization of Silkworm Pupae Protein for Preparation of ACE Inhibitory Peptides and Research on Its QSAR,R151
  20. Environmental Quantitative Structure-activity Relationship Studies on 2-hydroxy-1,4-naphthoquinones As Inhibitors of Psii and Triazole Fungicides,X132

CLC: > Medicine, health > Chinese Medicine > Of Pharmacy > Traditional Chinese medicine chemical
© 2012 www.DissertationTopic.Net  Mobile