Antiviral Research 50 (2001) 207 – 222
Exploring the role of the 5-position of TSAO-T. Synthesis
and anti -HIV evaluation of novel TSAO-T derivatives
Cristina Chamorro
a
, Marı ´a-Jesu´s Pe´rez-Pe´rez
a
, Fa´tima Rodrı ´guez-Barrios
b
,
Federico Gago
b
, Erik De Clercq
c
, Jan Balzarini
c
, Ana San-Fe´lix
a
,
Marı ´a-Jose´ Camarasa
a,
*
a
Instituto de Quı ´mica Me´dica (C.S.I.C.), C/Juan de la Ciera 3, E-28006 Madrid, Spain
b
Departamento de Farmacologı ´a, Uniersidad de Alcala´ , E-28871 Alcala´ de Henares, Madrid, Spain
c
Rega Institute for Medical Research, K.U. Leuen, Minderbroedersstraat 10, B-3000 Leuen, Belgium
Received 2 January 2001; accepted 3 April 2001
Abstract
Various analogues of the anti -HIV-1 agent TSAO-T, [1-[2,5-bis-O-(tert -butyldimethylsilyl)--D-ribofura-
nosyl]thymine]-3-spiro-5-(4-amino-1,2-oxathiole-2,2-dioxide) have been synthesized in which the 5-TBDMS
group has been replaced by alkyl-, alkenyl- or aromatic ether groups, substituted amines, carbamoyl or (thio)acyl
groups. The compounds synthesized were evaluated for their inhibitory effect on HIV-1 and HIV-2 replication in cell
culture. Replacement of the 5-TBDMS group by an acyl, aromatic or a cyclic moiety markedly diminish or even
eliminate the anti -HIV activity. However, the presence at that position of an alkyl or alkenyl chain, partially retain
antiviral activity. These observations suggest that the 5-TBDMS group of the TSAO molecule plays a crucial role.
© 2001 Elsevier Science B.V. All rights reserved.
Keywords: AIDS; Non-nucleoside HIV-1 RT inhibitors; Spironucleosides
www.elsevier.com/locate/antiviral
1. Introduction
A key target enzyme in the search for effective
drugs useful for AIDS therapy is the human
immunodeficiency virus (HIV) encoded reverse
transcriptase (RT) (Vaishnav and Wong-Staal,
1991; Kaltz and Skalka, 1993). An important
class of RT inhibitors is the non-nucleoside RT
inhibitors (NNRTIs) (De Clercq, 1993, 1996).
Among them, TSAO derivatives represent a
rather unique class of nucleoside analogues that
have been identified as highly specific non-com-
petitive inhibitors of the RNA-dependent DNA
polymerase function of RT (Balzarini et al.,
1992a,b,c; Camarasa et al., 1992; Pe´rez-Pe´rez et
al., 1992). In spite of their structural similarities to
nucleosides, and like the other NNRTIs, TSAO
analogues target a nonsubstrate binding site
(Balzarini et al., 1992c; Camarasa et al., 1992;
* Corresponding author. Fax: +34-91-5644853.
E-mail address: mj.camarasa@iqm.csic.es (M.-J. Camarasa).
0166-3542/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
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