5-플루오로우라실 프로드럭의 제조, 물리화학적 성질 및 항암효과

• 영문명: Synthesis, Physicochemical Properties and Antitumor Activity of 5-Fluorouracil Prodrugs
• 발행기관: 대한약학회
• 저자명: 지웅길(Ung Kil Jee) 이계원(Gye Won Lee)
• 간행물 정보: 『약학회지』제40권 제3호 (1996년), 279~292쪽, 전체 14쪽
• 주제분류: 의약학 > 기타의약학
• 파일형태: PDF
• 발행일자: 1996.06.30

영문 초록

To assess their stability as a prodrug of 5-fluorouracil (5-FU), four N-acyloxycarbonyl derivatives (1-(N-tert-butyloxycarbonyl)glycyloxymethyl-5-FU :BGFU, 1-(N-tert-butyloxycarbonyl)-leucyloxymethyl-5-FU:BLFU, 1-(N-tert-carbobenzyloxymethyl) glycyloxymethyl-5-FU:CGFU and 1-(N-tert-carbobenzlyoxymethyl)leucyloxymethyl-5-FU:CLFU) possessing differently protected amino acids, and two acetic acid derivatives (5FU-1-acetylpentane:FUAP and 5-FU-1-acetylhexane:FUAH) were synthesized and their physicochemical properties, hydrolysis kinetics, acute toxicity and antitumor activity were evaluated. The lipid-water partition coefficients of six 5-FU prodrugs were higher than that of 5-FU and their aqueous solubilities were in the following rank order; BGFU>FUAP>CGFU>BLFU>CLFU=FUAH. The hydrolysis of N-acyloxycarboyl derivatives, greater at higher pH, was enhanced in presence of liver homogenate or human plasma. Meanwhile, acetic acid ester derivatives, very stable, were hydrolyzed by liver homogenate. Absorption rate constants were 0.181, 0.121, 0.111, 0.168, 0.168, 0.116 and 0.125 hr-1 for 5-FU, BGFU, BLFU, CGFU, CLFU, FUAP and FUAH, respectively. The cytotoxicity of N-acyloxycarbonyl derivatives was 4 to 5 times lower than that of 5-FU, but that of acetic acid ester derivatives was negligeble. The LD50 values were 204, 325.97 (133.59, amount as 5-FU), 708.16 (262.13), 663.50 (211.77), 382.33 (192.54) and 272.33 (130.09) mg/kg for 5-FU, BGFU, CGFU, CLFU, FUAP and FUAH, respectively. While N-acyloxycarbonyl derivatives showed enhanced antitumor activity and therapeutic ratio (3.30, 3.06, 4.19, 3.11 and 1.81 for BGFU, BLFU, CGFU, CLFU and 5-FU, respectively), FUAH and FUAP showed a smaller therapeutic ratio (0.79 and 0.83).

키워드

5-FU 5-FU prodrugs pKa LD50 cytotoxicity partition coefficient hydrolysis antitum or activity therapeutic ratio solubility.