The Synthesls Of Hydroxyurea Derivatives、Antitumor Activity And General Pharmacology Study

Hydroxyurea(HU)is a specificity anitumor drug work on the cell cycle S phase.It used for the treatment of melanoma,Stomach cancer,Bowel cancer,Breast cancer,bladder cancer,head and neck pain,Malignant lymphoma,Primary liver cancer and the acute and chronic myeloid leukemia.It always combined with radiation and chemotherapy for the treatment of a brain tumor.In recent years,With the expansion of the clinical application,more and more HU,s new Clinical use were be found,For example,The cure for Sickle cell anemia therapy,β Mediterranean anemia therapy,psoriasis,the true red blood cells increased disease,Primary platelet increasing disease,HIV and so on.The mechanism of HU clinical application are similar,HU is a ribonucleotide reductase(RR)inhibitor,which is a key enzyme that catalyzes the reduction of ribonucleotides to deoxyribonucleotides and provides the building blocks for the denovo DNA synthesis in all dividing cells.HU has several disadvantages such as Side effects and low bioavailability in patient due to its big molecular polarity、small molecular size and low fat/water distribution coefficient,so its fat membrane penetration ability is weak.In this experiment,in order to increase the HU’s molecular weight and fat soluble,we reform the HU’s hydroxyl and the amino,and synthesis benzyloxyurea and N-substituted benzyloxyurea derivatives.This series of derivatives are base on the HU’s hydroxyl and the amino,Increase the replace aromatic.At last,we obtain 9 target compo-unds.The chemical structures of target compounds were identified by IR,ESI-MS and NMR spectra.The obtained benzyloxyurea and N-substituted benzyloxyurea derivatives were evaluated their anti-tumor activities in vitro to explore their anti-tumor effect against murine leukemia cell line L1210、human leukemia cell line K562 and human laryngreal carcinoma cell line HEP-2(This part of the experiment process omit,we just list for reference data).The experimental results indicated that some of the tested compounds were more efficient to inhibit the growth of tumor cells comparing with positive control drug hydroxyurea.Happily,the anti-tumor activities against HEP-2 of compounds HX-shu(IC50=17.30μmol/l)、HX-CN(IC50=11.86μmol/l)、HY-CN(IC50=10.70μmol/l)were more prominent than hydroxyurea(IC50= 192.00μmol/l).the anti-tumor activities against K562 of compounds HY-CN(IC50=0.14μmol/l)、HY-Cl(IC50=5.26μmol/l))were more prominent than hydroxyurea(IC50=73.60μmol/l).In the end,we have preliminarily analyzed the structure and activeity relation of target compounds basing on their anti-tumor activities.HY-11 was selected to do acute toxicity tests and pharmacodynamics of animals according to the results of in vitro efficacy.HY-11 was selected to do general pharm-acology research,according to the results of acute toxicity and pharmacod-ynamics.In this research,we measured the HY-11 in mice for the influence of the central nervous system、single and continuous irrigation stomach of HY-11 suspen-sion liduid in order to measure the influence of rabbit’s cardiovascular system and respiratory system.