Synthesis of AZA analogues of TSAO

Article abstract of DOI:10.1081/NCN-120022690

TSAO derivatives which were first synthesized in 1992 have shown strong inhibitory effect and selectivity against HIV-1 (Camarasa, M.J.; Perez-Perez, M.J.; San-Felix, A.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992, 35, 2721-2727). The structure-activ

Full text of DOI:10.1081/NCN-120022690

This article was downloaded by: [Fondren Library, Rice University ]
On: 17 November 2014, At: 00:35
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Nucleosides, Nucleotides and Nucleic Acids
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lncn20
Synthesis of AZA Analogues of TSAO
Albert Nguyen Van Nhien a , Cyrille Tomassi a , Christophe Len a , José Luis Marco-Contelles b
& Denis Postel a c
a Laboratoire des Glucides , Université de Picardie-Jules Verne , Amiens, France
b Laboratorio de Los Radicales Libres Instituto de Química Orgánica General, Juan de la
Cierva , Madrid, Spain
c Laboratoire des Glucides , Université de Picardie, 33, rue Saint Leu , 80039, Amiens,
France
Published online: 31 Aug 2006.
To cite this article: Albert Nguyen Van Nhien , Cyrille Tomassi , Christophe Len , José Luis Marco-Contelles & Denis Postel
(2003) Synthesis of AZA Analogues of TSAO, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 939-941, DOI: 10.1081/
NCN-120022690
To link to this article: http://dx.doi.org/10.1081/NCN-120022690
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 939–941, 2003
Synthesis of AZA Analogues of TSAO
Albert Nguyen Van Nhien,1 Cyrille Tomassi,1 Christophe Len,1
2
Jose Luis Marco-Contelles, and Denis Postel
1,
*
´
1
´
Laboratoire des Glucides, Universite de Picardie-Jules Verne, Amiens, France
Laboratorio de Los Radicales Libres Instituto de Quımica Organica General,
2
´
´
Juan de la Cierva, Madrid, Spain
ABSTRACT
TSAO derivatives which were first synthesized in 1992 have shown strong inhibi-
´
´
tory effect and selectivity against HIV-1 (Camarasa, M.J.; Perez-Perez, M.J.;
San-Felix, A.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992, 35, 2721–2727).
´
The structure-activity relationship of these derivatives has shown strong binding
between the amino acids constituting the reverse transcriptase and the different
pharmacophore (tert-butyldimethylsilyl group, amino and sulfonate groups of
´
´
´
the TSAO derivatives) (Camarasa, M.J.; San-Felix, A.; Perez-Perez, M.J.;
´
´
Velazquez, S., Alvarez, R.; Chamorro, C.; Jimeno, M.L.; Perez, C.; Gago, F.;
De Clercq, E.; Balzarini, J. J. Carbohydr. Chem. 2000, 19, 6403–6406). We
described the synthesis of an original TSAO analogue where, basically, the
O-100 atom is replaced by a nitrogen atom.
´
*Correspondence: Denis Postel, Laboratoire des Glucides, Universite de Picardie, 33,
rue Saint Leu, 80039 Amiens, France; Fax: +33 3 2282 7568; E-mail: denis.postel@
sc.u-picardie.fr.
939
DOI: 10.1081/NCN-120022690
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

940
Nguyen Van Nhien et al.
Scheme 1. Reagents and conditions: (i) SO(Im)2, THF; (ii) silylated thymine, 130ꢀC; (iii)
TBDMSCl, imidazole, DMF; (iv) MeI, K2CO3, MeCN; (v) Cs2CO3, MeCN; (vi) C6H10-
Pd(OH)2, EtOH.
Starting from glyco-a-aminonitrile precursors which have been intensively stu-
died in our laboratory and obtained in a stereospecific way,[3,4] successive mesylation
and deprotection of a ribo derivative lead to the sulfonamido derivative 1 with an
overall yield higher than 95%. Attempts to introduce a nucleic base such as thymine
by a Vorbruggen procedure did not lead to the corresponding nucleoside. This could
¨
be obtained, however, by the fusion method. The 1,2-O-sulfinyle derivative was pre-
pared with SO(Im)2 in THF with about 85% yield as its exo=endo cyclic form.
Finally, condensation of a silylated thymine at 130ꢀC with the 1,2-O-sulfinyle
resulted in nucleoside 2 with 82% yield. Methylation on the N-positions created
the precursor for the CSIC reaction. Cyclisation with Cs2CO3 afforded 45% yield
of the isothiazolic derivative 3. Deprotection of the benzyl group with C6H10-
Pd(OH)2 followed by silylation with TBDMSCl gave the A-TSAO-m3T (4) in 65%
yield.
In a similar way, A-TSAO-T analogue (non alkylated base) was obtained by
selective protection of thymine with a BOC group. Then, the cyclisation followed
by the one-pot deprotection of both the benzyl and BOC groups with C6H10-
Pd(OH)2 gave the leading compound, after silylation, with 55% yield.
Biological tests have shown selective inhibition on HIV-1 RT.
Investigations to obtain both non alkylated N-sulfonamide and substitution
on the 500-C are also in progress. In order to investigate SARs different substitu-
ents should be introduced on both the nucleic base and the sulfonamide cyclic
moiety.
REFERENCES
´
´
´
1. Camarasa, M.J.; Perez-Perez, M.J.; San-Felix, A.; Balzarini, J.; De Clercq, E.
J. Med. Chem. 1992, 35, 2721–2727.
´
2. Camarasa, M.J.; San-Felix, A.; Perez-Perez, M.J.; Velazquez, S.; Alvarez, R.;
Chamorro, C.; Jimeno, M.L.; Perez, C.; Gago, F.; De Clercq, E.; Balzarini, J.
´
´
´
´
J. Carbohydr. Chem. 2000, 19, 451–469.

Synthesis of AZA Analogues of TSAO
941
3. Postel, D.; Nguyen Van Nhien, A.; Pillon, M.; Villa, P.; Ronco, G. Tetrahedron
Letters 2000, 41, 6403–6406.
4. Postel, D.; Nguyen Van Nhien, A.; Villa, P.; Ronco, G. Tetrahedron Letters
2001, 42, 593–595.