Design, Synthesis And Investigation Of Bone Affinity Of The Conjugate Of 5-Fluorouracil And Hydroxybisphosphonate

Bone tumor are common diseases, which comprise primary and metastatic types, and treated by the combination therapy of surgical resection, radiotherapy and chemotherapy. As one of the most important treatment, chemotherapy plays an important role. However, a major problem in chemotherapy that limits its use is lack of sufficient selectivity, which leads to high toxicity and serious side-effect. To solve this problem, targeting therapy has heen proposed, namely, the bone-targeting carries are conjugated with antitumor agent, as a prodrug, the conjugate can target the bone tumor to increase selectivity and reduce toxicity and side-effect of antitumor agent.In this dissertation, some novel bone-targeting antitumor agents were designed through the conjugation of hydroxybisphosphonate(HBP) with antitumor agent. Series 1-3 aim compounds(T₁^T₁₂)were designed through the conjugation of HBP and 5-Fu with carbon chain in different length at N_1^- , N_3^- and O_4^- -position respectively. In addition, series 4 aim compounds(T₁₃ T₁₄) were designed through the combination of HBP with Chloramphenalanum and Clorambucilum by "non-bridge" way.In this dissertation, N₁-substituted 5-Fu derivatives containing 2-5 carbon alkanoic were prepared. The reaction were examind by HPLC, the result showed that a high yield of the N₁-substituted product could be obtained through the addition of excessive amount of 5-Fu.In this dissertation, N₃-substituted 5-Fu derivatives containing 2-5 carbon alkanoic acid were prepared. 5-Fu were protected with tert-butoxycarbonyl(BOC) at N₁-position, then the product reacted with haloid ether and deprotected in turn, through the "one-pot" method, N₃-alkanoic acid substituted 5-Fu derivatives...