Synthesis of Ara-C Prodrugs Containing D-phenylglycine or D-p- hydroxyphenylglycine

• Main Authors: Ho,Ming-Chun, 何明純
• Other Authors: Wang,Hui-Po
• Format: Others
• Language: zh-TW
• Published: 1996
• Online Access: http://ndltd.ncl.edu.tw/handle/07486673449512819124

碩士 === 國立臺灣大學 === 藥學研究所 === 84 === Ara-C自1960年代以來一直是治療人類急性骨髓細胞性白血病(acute lym- phogenous leukemia)及急性淋巴細胞性白血病(acute lymphogenous leukemia)的首選藥物。然而此藥僅能注射，口服並不吸收 ；由於它在血中易受cytidine deaminase作用而快速去胺基( deamination)代謝，使得此藥在血中之半衰期很短，只有12分鐘左右。目 前臨床上多使用靜脈輸注 (IV infusion)或高劑量注射方式(bolus)投藥 ，造成骨髓抑制胃腸障礙及肝肺腎等之毒性。為減緩其結構中cytosine位 置胺基被代謝速度，配合臨床上發展小劑量多次投予Ara-C之療程趨勢， 因而考慮以先驅藥(prodrug)床上發展小劑量多次投予ra-e 生物鹼的成分 研究。的形式來重新修飾結構。近年來許多研究證據顯示，小腸中氫離子 共運的雙胜■媒介載體系統(H+ coupled dipeptide-mediated carrier transport system)在口服吸收的 amino-b-lactam抗生素和血管升壓素轉 化■(angiotensin converting enzyme，ACE)抑制劑之小腸吸收機轉中扮 演重要的角色，因而考慮以此雙生太媒介載體系統作為Ara-C口服吸收之 腸道輸遞系統(oral drug deli- very system)。 D-phenylglycine或D- p-hydroxyphenylglycin是目前可以口服的amino-b -lactam藥物的共同構 造，此二分子可能扮演著與雙胜■媒介載體系統親合的重要的角色，可能 可作為其它藥物利用此輸遞系統通過腸道的一個工具(delivery tool。因 此，我們選擇以D-phenylglycine，D-phenylgly- cine-L-proline，D-p- hyroxyphenylglycine，D-p-hyroxyphenylglycine為此輸遞工具，試圖探 討這些先驅藥是否可口服吸收，以及是否因胺基被保護而可減緩其代謝。 我們將Ara-C之C5''的OH基以trityl保護，做成5''-trityl-ara-C，另將D- phenylglycine，D-phenylglycine-L-proline，D-p-hyroxyphenylgly- cine，和D-p-hyroxyphenylglycine做成含N(Boc)保護基的衍生物，再分 別接上5''-trityl-ara-C，做成中間體，最後以飽和之HCl/CH2Cl2同時切 除trityl及N(Boc)保護基，得到所要的四個最終產物。 Ara-C, is the drug of choice for acute myelogenous leukemia and acute lymphogenous leukemia. However poor oral absorption has li- limited its use in injectable form. Even as an injection, serious toxic effects, such as myelosuppression, nausea, vomiting made clinical management of therapeutical regimen difficult. Moreover, the high rate of deamination caused by cytidine deaminase in plasma render its bio ogical half life as short as 12 mins. Con- sequently, a therapeutic regimen with frequent administration of low dose of Ara-C becomes the trend. this prompted us to mo- dified the structure of ara-C by developing its prodrugs. Recent reports indicate some amino-β- antibiotics were absorbed in the small intestine via a H+- coupled dipeptide-mediated carr- ier transport system which majorly exists in the brush border membrane. Analysis of the chemical structures of these orally absorbed amino-β-lactams revealed that D-phenylglycine or D-p- hydroxyphenylglycine is the common moiety. These amino acids might have strong affinity for the carrier protein and be a use- ful tool for delivering poorly absorbed drugs through the intes- tine via this transport system. For designing of ara-c prodrugs, we choose D- phenylglycine and D-p-hydroxyphenylglycine to attach onto ara-C either directly at its 4-NH2 group or via another amino acid, proline. The 5''OH group of ara-C was protected by reaction with trityl chloride, then coupled with N(Boc)-protecting derivatives of D- phenylglycine, D-p-hydroxyphenylglycine, D- phenylglycine-L-pro- line and D-p-hydroxyphenylglycine-L- proline with DCC affored the intermediates. Subsequent treatment with a saturaetd HCl/CH2Cl2 solution to cleave the trityl and Boc groups affored the desired derivatives as ara-C prodrugs. The stability test and oral absor- ption efficancies of the prodrugs need further investigation.