Synthesis And Antitumor Activity Evaluation Of Polyamine Conjugations

Tumor is still a lethal disease threatening human beings and it has become the major cause which resulted in death of lives.Chemotherapy is one of the most rapidly developing strategies in cancer therapy.To date,although a large number of drugs have been developed and used in neoplasm therapy,they always exhibit many drawbacks such as low tumor-target and multidrug resistance and bring out severe side effects in clinical use.Thus,their application is greatly limited.Determination of the drug target becomes important to breach such trouble and be helpful to develop new efficient drugs.With the development of modern technology and molecular biochemistry,the research on tumor target has become more and more active in anticancer drugs.Among them,polyamine is one of the hot topics in the development of antineoplastic drugs. Polyamines are ubiquitous constituents of eukaryotic cells and play a key role in cellular physiology.The pathways for polyamine metabolism have been elucidated and provided a target for the design of antitumor agents.The polyamine transporter could recognize polyamine and its analogues,and preferentially ferry them into cells.Thus, the polyamine backbone could act as potential carriers for drug delivery.As a result, the tumor targeting of drugs were improved.Based on the structure-activity relationship of polyamine analogues,we reported in this dissertation the design and synthesis of two series of linear polyamine conjugations and their investigation on polyamine transporter affinity using AN-44 as the lead compound.Compounds T1-7 were designed for comparison of the different polyamine chains,and T8-15 were evaluated for the influence of dissimilar pharmacophore conjugated.Moreover,we reported the structural modification of natural products T16-32 and investigated the synergistic effect on anticancer drug.We employed various synthetic routes in efficient construction of polyamine backbones.The classical Garbiel procedure was performed during the synthesis of target compounds using MtsC1 or Boc₂O as the protection agents.During the synthesis of T1-7,the side reaction was detected,and the title compound was obtained with "one-pot" amelioration,and the yield was also improved unexpectedly.In this thesis,amount to 84 compounds were synthesized including 74 initial ones, their chemical structures were confirmed by MS,¹H/¹³C NMR and elemental analysis.The in vitro antitumor activities of target compounds were investigated in L1210, CHO,HeLa,B16 and K562 tumor cells,and the results revealed that the compound T6, from T1-7 series,could be recognized by PAT,and could act as potential tumor targeting agent for further evaluation.Among the T16-32 series,compound T16 was the most potent agent which showed prominent synergistic effect on VBL.Its synergy coefficient was 2.07 which was higher than that of reference compound SDB.With T6 in hand,we further investigated the antitumor activity both on enzyme and whole animal levels.It turned out that T6 had obvious effects on TOPOâ…¡and ODC,and that T6 could induce the apoptosis of B16 tumor cells.The in vivo antitumor activity revealed that T6 could not only inhibit the tumor growth,but also obviously increase the lifespan of tumor-bear mice.For example,at the dose of 10 mg/kg/d,the tumor growth was inhibited by 56.9%and the mean survival time of tumor-bear mice was increased to 2.29 folds in comparison with the control.