Synthesis of Nonclassical Antifolate Analogues

• Main Authors: Yen-Lin Huang, 黃妍齡
• Other Authors: Chi-Ming Chen
• Format: Others
• Language: zh-TW
• Published: 2000
• Online Access: http://ndltd.ncl.edu.tw/handle/06241879227556304871

碩士 === 台北醫學院 === 藥學研究所 === 88 === Abstract Synthesis of Nonclassical Antifolate Analogues Several classical antifolates (such as methotrexate) are inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and are currently used clinically for treatment of cancer patient. However, the problems associated with the clinical use of these compounds are: 1) undesirable toxicity to rapidly proliferating normal tissues, such as bone marrow and gastrointestinal mucosa; and 2) the development of drug resistance. To overcome these problems, several non-classical antifolates (such as trimetrexate and piritrexim) were later developed and were found to have potent antitumor activity. Recently, we have synthesized a series of non-classical antifolate derivatives for antitumor evaluation and reported herein. The non-classical antifolates ( 62-76 ) were synthesized starting from the condensation of 1,4-dibromo-2-butanol with various substituted anilines to give 1-phenyl-3-pyrrolidinols, which were oxidized (DCC/DMSO) to yield 1-phenyl-3-pyrrolidinones. The ketones were reacted with malononitrile or ethyl cyanoacetate to afford 3-(dicyanomethylene)-1-phenylpyrrolidines or 3-[cyano(ethoxycarbonyl) methylene]-1-phenylpyrrolidines, which were then converted into the desired compounds ( 62-76 ) via reduction (NaCNBH3) and followed by condensation with guanidine carbonate. The structures of these synthetic analogues are consistent with the spectral data of IR, PMR, CMR, Mass spectra and Element analysis. Sixteen compounds including Methotrexate and our target compounds were evaluted the in vitro cytotoxicity against four human tumor cell growth. ( MOLT-4、H23、H23/0.3 and COLO 205 ) The result indicated that compound 63, 64 and 65 have stronger effects in MOLT-4 than other synthetic compounds, but less active than Methotrexate.