Phosphoralaninate pronucleotides of pyrimidine methylenecyclopropane analogues of nucleosides: Synthesis and antiviral activity

被引：6

作者：

Ambrose, A

Zemlicka, J ^{[1
]}

Kern, E

Drach, J

Gullen, E

Cheng, YC

机构：

[1] Wayne State Univ, Sch Med, Dept Chem, Dev Therapeut Program,Barbara Ann Karmanos Canc I, Detroit, MI 48201 USA

[2] Univ Alabama, Sch Med, Dept Pediat, Birmingham, AL USA

[3] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA

[4] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA

来源：

NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS | 2005年 / 24卷 / 10-12期

关键词：

antivirals; HCMV; EBV; VZV; methylenecyclopropane analogues; pronucleotides; phenyl phosphoralaninates; prodrugs;

D O I：

10.1080/15257770500266867

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The Z - and E -thymine and cytosine pronucleotides 3d, 4d, 3e, and 4e of methylenecyclopropane nucleosides analogues were synthesized, evaluated for their antiviral activity against human cytomegalovirus (HCMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human immunodeficiency virus type 1 (HSV-1), and hepatitis B virus (HBV) and their potency was compared with the parent compounds 1d, 2d, 1e, and 2e. Prodrugs 3d and 4d were obtained by phosphorylation of parent analogues 1d or 2d with reagent 8. A similar phosphorylation of N 4 -benzoylcytosine methylenecyclopropanes 9a and 9b gave intermediates 11a and 11b. Deprotection with hydrazine in pyridine-acetic acid gave pronucleotides 3e and 4e. The Z -cytosine analogue 3e was active against HCMV and EBV. The cytosine E -isomer 4e was moderately effective against EBV.

引用

页码：1763 / 1774

页数：12

共 18 条

[1] Anti-HIV and anti-HBV activity and resistance profile of 2',3'-dideoxy-3'-thiacytidine (3TC) and its arylphosphoramidate derivative CF 1109 [J].

Balzarini, J ;

Wedgwood, O ;

Kruining, J ;

Pelemans, H ;

Heijtink, R ;

DeClercq, E ;

McGuigan, C .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1996, 225 (02) :363-369

[2]

Cahard D, 2004, MINI-REV MED CHEM, V4, P371

[3] Revision of absolute configuration of enantiomeric (methylenecyclopropyl)carbinols obtained from (R)-(-)- and (S)-(+)-epichlorohydrin and methylenetriphenylphosphorane.: Implications for reaction mechanism and improved synthesis of antiviral methylenecyclopropane analogues of nucleosides [J].

Chen, XC ;

Zemlicka, J .

JOURNAL OF ORGANIC CHEMISTRY, 2002, 67 (01) :286-289

[4]

IWAI I, 1968, SYNTHETIC PROCEDURES, V1, P388

[5] Efficacy of methylenecyclopropane analogs of nucleosides against herpesvirus replication in vitro [J].

Kushner, NL ;

Williams, SL ;

Hartline, CB ;

Harden, EA ;

Bidanset, DJ ;

Chen, XC ;

Zemlicka, J ;

Kern, ER .

NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, 2003, 22 (12) :2105-2119

[6]

LETSINGER RL, 1968, TETRAHEDRON LETT, P2621

[7] Phosphoramidate derivatives of d4T with improved anti-HIV efficacy retain full activity in thymidine kinase-deficient cells [J].

McGuigan, C ;

Cahard, D ;

Sheeka, HM ;

DeClercq, E ;

Balzarini, J .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1996, 6 (10) :1183-1186

[8]

Qiu YL, 1998, SYNTHESIS-STUTTGART, P1447

[9] Synthesis and antiviral activity of phosphoralaninate derivatives of methylenecyclopropane analogues of nucleosides [J].

Qiu, YL ;

Ptak, RG ;

Breitenbach, JM ;

Lin, JS ;

Cheng, YC ;

Drach, JC ;

Kern, ER ;

Zemlicka, J .

ANTIVIRAL RESEARCH, 1999, 43 (01) :37-53

[10] (Z)- and (E)-2-((hydroxymethyl)cyclopropylidene)methyladenine and -guanine.: New nucleoside analogues with a broad-spectrum antiviral activity [J].

Qiu, YL ;

Ksebati, MB ;

Ptak, RG ;

Fan, BY ;

Breitenbach, JM ;

Lin, JS ;

Cheng, YC ;

Kern, ER ;

Drach, JC ;

Zemlicka, J .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (01) :10-23

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