| Ribonucleotide reductase (RR) is popularly found in bacteria, yeast, cells of human and other cell systems. Research shows that RR is the only enzyme that provides dandy in the process of DNA replication and repair, which was called the rate-limiting enzyme of DNA biosynthesis. RR highly expresses in many malignant tumors. Research in vitro indicates that RR's excessive amplification is concerned with proliferation of tumor progression. So RR is considered one of the most important targets for chemotherapeutics.There are many inhibitors against RR, but only hydroxyurea(HU) which is also the only antineophastic agent of RR inhibitor is applied to the clinic, primarily curing chronic myelocytic leukemia (CML), melanoma and polycythemia vera disease. Additionally, it also plays a positive role in curing squamous cell carcinomas in the head and neck and relapsed metastasis ovarian cancer ,etc. Recently, people have found that it has certain effect on sickle cell anemia, beta-thalassemia and psoriasis, and so on. It is also reported that HU has also been used for the treatment of AIDS in combination with didanosine ,showing no viral rebound after 1 year's treatment.Therapeutic application of HU in patients has several disadvantages such as short half-life (1.9-3.9h) due to its small molecular size (MW=76.06) and extremely polar nature (logPO/W=-1.80),the necessity of using high dosage (80 mg/kg every third day or 20-30 mg/kg daily) and the rapid development of resistance. These disadvantages could lead to an increase in toxicities and side effects and a reduction in bioavailability. Using HU as a lead compound, this present study was performed to design drugs and modify structures according to their structural characteristics and SAR for finding an antitumor activity material with strong pharmacological specificity, less toxicities and side effects. The main contents of this essay are summarized as follows:1. We designed and synthesized the prodrug of benzyloxy-urea series and N-benzyl-N-benzyloxy-urea series by using HU as a lead compound. These target compounds were add aroma or substituent aroma on the basis of the HU, making compounds'molecular weight and liposolubility increase and space structure change. We calculated ClogP of prodrug of hydroxyurea derivatives by using ChemDraw Ultra 7.0 and found that ClogP of prodrug of hydroxyurea derivatives was significantly greater than HU. So liposolubility of design and synthesis hydroxyurea derivatives obviously enhances comparing to HU. Consequently, it is a hope that these compounds have a reduction in toxicities and side effects and an increase in bioavailability. Meanwhile, The prodrug of hydroxyurea derivatives can release active ingredients after being degrdned by the Mixed Function Oxidase in vivo, which lead to the adoption of the modified structure, hopefully extending the half life of hydroxyurea.2. We synthesized the prodrug of benzyloxy-urea series and N-benzyl-N-benzyloxy-urea series, and eventually got 12 target compounds, their structures were identified by IR,MS and NMR. Six compounds of them are the new compounds which have not yet been reported in the literature.3. We used these target compounds to make the antitumor activity test in vitro for lymphoid leukemia L1210 and the cell lines Tca8113 of human's tongue cancer through the classic MTT and SRB assays. Result shows that the most derivatives of hydroxyurea have stronger inhibition ratio than hydroxyurea. In the test of cell lines Tca8113, No. HY-10 has the strongest inhibition ratio (IC50=5.29×10-7M, SRB assay), which is about tens of thousands of times than HU.4. The results of preliminary anti-tumor activity test in vitro revealed a number of structure-activity relationship rule. We found from the two tests that the estimated value of ClogP was positive proportional to the anti-tumor activity of the derivatives. So, we can draw a conclusion that the liposolubility of compounds has significant influence on its anti-tumor activity, which provides an important reference for studying the design, synthesis and the SAR of new hydroxyurea derivates'anti-tumor activity.
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