非傳統葉酸拮抗劑之合成研究
Synthesis of Nonclassical Antifolate Analogues
中文摘要 非傳統葉酸拮抗劑之合成研究 數種傳統性葉酸拮抗劑 ( 如 Methotrexate ) 其作用機轉已被證實為二氫葉酸還 原 或胸腺核 酸合成 之抑制劑，並且也已廣泛的應用於癌症疾病的治療。然 而這些藥物於使用上卻受下列因素所限制：1) 藥物對正常快速增生之組織 (例 如骨髓細胞、胃腸黏膜細胞) 容易產生毒性；2) 細胞易對藥物產生抗藥性，為 了克服這些缺點，許多非傳統性葉酸拮抗劑 (如 Trimetrexate 與 Piritrexim) 陸續 被研究發展，且發現具有相當之抗癌活性。因此，我們設計並化學合成製備一系 列非傳統性葉酸拮抗劑，以進行抗癌活性之測定。 所欲合成之非傳統性葉酸拮抗劑 ( 62-76 ) 之製備乃以 1,4-dibromo-2-butanol 為 原料，與具各種不同取代基之 anilines 進行縮合反應，生成1-phenyl-3-pyrrolidinols，再以 DCC / DMSO 氧化得到 1-phenyl-3-pyrrolidinones。 接著將所合成之酮類中間產物與 malononitrile 或 ethyl cyanoacetate 經
Knoevenagel 反應，即可得到 3-(dicyanomethylene)-1-phenyl-pyrrolidines 及 3-[cyano(ethoxycarbonyl)-methylene]-1-phenyl-pyrroli-dines。此二類之化合物再經 NaCNBH3 還原及與 guanidine 之縮合反應，即可成功合成標的化合物 ( 62-76 )。 合成的 15 種化合物均經紅外光譜、氫譜、碳譜、質譜及元素分析等鑑定結構。 Methotrexate 與我們合成之十五個化合物是以 MOLT-4、H23、H23/0.3 及 COLO 205 四種癌細胞株作體外細胞毒性之測試。結果顯示化合物 63, 64 及 65 對於抑 制 MOLT-4 細胞株之生長具有較佳的細胞毒性，雖然其作用仍較 Methotrexate 為 差。
英文摘要
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.
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.
