Synthesis of a novel esterase-sensitive cyclic prodrug of a hexapeptide using an (acyloxy)alkoxy promoiety

被引:45
作者
Gangwar, S [1 ]
Pauletti, GM [1 ]
Siahaan, TJ [1 ]
Stella, VJ [1 ]
Borchardt, RT [1 ]
机构
[1] UNIV KANSAS, DEPT PHARMACEUT CHEM, LAWRENCE, KS 66047 USA
关键词
D O I
10.1021/jo961696a
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
Synthetic methodology for preparing novel esterase-sensitive cyclic prodrugs of peptides with increased protease stability and cell membrane permeability compared to linear peptides is described. Cyclic prodrug 1 of the hexapeptide H-Trp-Ala-Gly-Gly-Asp-Ala-OH linked by the N-terminal amino group to the C-terminal carboxyl group via an (acyloxy)alkoxy promoiety was synthesized. A convergent synthetic approach involving Boc[[(alaninyloxy)methyl]carbonyl]-N-tryptophan (2) and H-Ala-Gly-Gly-Asp(OBzl)-OTce (3) was used. The key fragment 2 has the promoiety inserted between the Ala and the Trp residues. Fragment 3 was synthesized by a solution-phase approach using standard Boc-amino acid chemistry. These fragments were coupled to produce the protected linear hexapeptide, which after deprotection was cyclized using standard high-dilution techniques to yield cyclic prodrug 1. In pH 7.4 buffer (HBSS) at 37 degrees C, cyclic prodrug 1 was shown to degrade quantitatively to the hexapeptide (t(1/2) = 206 +/- 11 min). The rate of hydrolysis of cyclic prodrug 1 was significantly faster in human blood (t(1/2) = 132 +/- 4 min) than in HBSS. Paraoxon, a known inhibitor of esterases, slowed this hydrolysis of cyclic prodrug 1 to a value (t(1/2) = 198 +/- 9 min) comparable to the chemical stability. In human blood, cyclic prodrug 1 was shown to be 25-fold more stable than the linear hexapeptide.
引用
收藏
页码:1356 / 1362
页数:7
相关论文
共 48 条
[1]   (ACYLOXY)ALKYL CARBAMATE PRODRUGS OF NORFLOXACIN [J].
ALEXANDER, J ;
FROMTLING, RA ;
BLAND, JA ;
PELAK, BA ;
GILFILLAN, EC .
JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (01) :78-81
[2]   (ACYLOXY)ALKYL CARBAMATES AS NOVEL BIOREVERSIBLE PRODRUGS FOR AMINES - INCREASED PERMEATION THROUGH BIOLOGICAL-MEMBRANES [J].
ALEXANDER, J ;
CARGILL, R ;
MICHELSON, SR ;
SCHWAM, H .
JOURNAL OF MEDICINAL CHEMISTRY, 1988, 31 (02) :318-322
[3]  
AMIDON GL, 1994, ANNU REV PHARMACOL, V34, P321
[4]   THE LACTONIZATION OF 2'-HYDROXYHYDROCINNAMIC ACID-AMIDES - A POTENTIAL PRODRUG FOR AMINES [J].
AMSBERRY, KL ;
BORCHARDT, RT .
JOURNAL OF ORGANIC CHEMISTRY, 1990, 55 (23) :5867-5877
[5]   AMINE PRODRUGS WHICH UTILIZE HYDROXY AMIDE LACTONIZATION .2. A POTENTIAL ESTERASE-SENSITIVE AMIDE PRODRUG [J].
AMSBERRY, KL ;
GERSTENBERGER, AE ;
BORCHARDT, RT .
PHARMACEUTICAL RESEARCH, 1991, 8 (04) :455-461
[6]  
Atherton E, 1989, SOLID PHASE PEPTIDE, P25
[7]  
AUDUS KL, 1992, ADV DRUG RES, V23, P1
[8]  
BOCCI V, 1990, ADV DRUG DELIVERY RE, V4, P149
[9]  
Bodansky M, 1994, PRACTICE PEPTIDE SYN, P75
[10]  
BUNDGAARD H, 1992, ADV DRUG DELIVER REV, V8, P1, DOI 10.1016/0169-409X(92)90014-H