Second-generation cycloSal-d4TMP pronucleotides bearing esterase-cleavable sites -: the "trapping" concept

被引：23

作者：

Meier, C

Ducho, C

Jessen, H

Vukadinovic-Tenter, D

Balzarini, J

机构：

[1] Univ Hamburg, Inst Organ Chem, D-20146 Hamburg, Germany

[2] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium

来源：

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY | 2006年 / 2006卷 / 01期

关键词：

antiviral agents; bioorganic chemistry; nucleosides; phosphates; pronucleotides;

D O I：

10.1002/ejoc.200500490

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

An extension of the cycloSal-pronucleotide approach is presented. Attachment of an enzyme-cleavable ester/acylal group to the cycloSal-d4TMP triesters should allow these compounds to be trapped intracellularly after cleavage. The ester/acylal groups were introduced in the 3- or 5-position of the cycloSal ring system, and surprising differences were observed in hydrolysis studies in CEM cell extracts with respect to the ester/acylal moiety. While acetyl and levulinyl esters were readily cleaved, alkyl esters of cycloSal-d4TMP acids proved to be resistant to enzymatic cleavage. In contrast, AM-, POM- and POC-acylals were rapidly cleaved in the extracts, leading to cycloSal-d4TMP acids. The antiviral activity of the compounds against HIV is also presented. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006).

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页码：197 / 206

页数：10

相关论文

共 26 条

[1] Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) prodrugs [J].

Arimilli, MN ;

Kim, CU ;

Dougherty, J ;

Mulato, A ;

Oliyai, R ;

Shaw, JP ;

Cundy, KC ;

Bischofberger, N .

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 1997, 8 (06) :557-564

[2] Intracellular metabolism of CycloSaligenyl 3′-azido-2′,3′-dideoxythymidine monophosphate, a prodrug of 3′-azido-2′,3′-dideoxythymidine (zidovudine) [J].

Balzarini, J ;

Naesens, L ;

Aquaro, S ;

Knispel, T ;

Perno, CF ;

De Clercq, E ;

Meier, C .

MOLECULAR PHARMACOLOGY, 1999, 56 (06) :1354-1361

[3] Antiviral activity of cyclosaligenyl prodrugs of acyclovir, carbovir and abacavir [J].

Balzarini, J ;

Haller-Meier, F ;

De Clercq, E ;

Meier, C .

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 2001, 12 (05) :301-306

[4] ANTI-RETROVIRUS ACTIVITY OF 3'-FLUORO-SUBSTITUTED AND 3'-AZIDO-SUBSTITUTED PYRIMIDINE 2',3'-DIDEOXYNUCLEOSIDE ANALOGS [J].

BALZARINI, J ;

BABA, M ;

PAUWELS, R ;

HERDEWIJN, P ;

DECLERCO, E .

BIOCHEMICAL PHARMACOLOGY, 1988, 37 (14) :2847-2856

[5]

BALZARINI J, 1994, BIOCHEM PHARMACOL, V49, P751

[6] SYNTHESIS AND LTB(4) RECEPTOR ANTAGONIST ACTIVITIES OF THE NATURALLY-OCCURRING LTB(4) RECEPTOR ANTAGONIST LEUCETTAMINE-A AND RELATED ANALOGS [J].

BOEHM, JC ;

GLEASON, JG ;

PENDRAK, I ;

SARAU, HM ;

SCHMIDT, DB ;

FOLEY, JJ ;

KINGSBURY, WD .

JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (22) :3333-3340

[7] DIE REAKTION VON CARBONSAUREN MIT ACETALEN DES N,N-DIMETHYLFORMAMIDS - EINE VERESTERUNGSMETHODE [J].

BRECHBUHLER, H ;

BUCHI, H ;

HATZ, E ;

SCHREIBER, J ;

ESCHENMOSER, A .

HELVETICA CHIMICA ACTA, 1965, 48 (07) :1746-+

[8] Selective monoacetylation of unsymmetrical diols catalyzed by silica gel-supported sodium hydrogen sulfate [J].

Breton, GW .

JOURNAL OF ORGANIC CHEMISTRY, 1997, 62 (25) :8952-8954

[9]

Ducho Christian, 2002, Antivir Chem Chemother, V13, P129

[10] cycloSal-pronucleotides of 2′,3′-dideoxyadenosine and 2′,3′-dideoxy-2′,3′-didehydroadenosine:: Synthesis and antiviral evaluation of a highly efficient nucleotide delivery system [J].

Meier, C ;

Knispel, T ;

De Clercq, E ;

Balzarini, J .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (09) :1604-1614