Ring opening reactions: Synthesis of AICAR analogs as potential antimetabolite agents

Article abstract of DOI:10.1081/NCN-200059860

In an attempt to improve the A_2A selectivity of the 2-(aryl)alkylthio derivatives of adenosine, we planned the synthesis of the corresponding derivatives of the 5′-N-ethylcarboxamidoadenosine (NECA). For this purpose, we designed the synthesis of 2-mercapto-NECA to be pursued by means of an opening-closure method. We obtained the open AICAR analog; however, ring closure efforts failed to give the desired compound. The newly synthesized AICAR derivative could potentially be endowed with antiviral or antitumoral activity. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/NCN-200059860

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RING OPENING REACTIONS: SYNTHESIS OF AICAR
ANALOGS AS POTENTIAL ANTIMETABOLITE AGENTS
S. Costanzi a , C. Lambertucci a , F. R. Portino a , R. Volpini a , S. Vittori a & G. Cristalli a
a Dipartimento di Scienze Chimiche , University of Camerino , Camerino, Italy
Published online: 15 Nov 2011.
To cite this article: S. Costanzi , C. Lambertucci , F. R. Portino , R. Volpini , S. Vittori & G. Cristalli (2005) RING OPENING
REACTIONS: SYNTHESIS OF AICAR ANALOGS AS POTENTIAL ANTIMETABOLITE AGENTS, Nucleosides, Nucleotides and Nucleic
Acids, 24:5-7, 415-418, DOI: 10.1081/NCN-200059860
To link to this article: http://dx.doi.org/10.1081/NCN-200059860
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):415–418, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200059860
RING OPENING REACTIONS: SYNTHESIS OF AICAR ANALOGS AS
POTENTIAL ANTIMETABOLITE AGENTS
S. Costanzi, C. Lambertucci, F. R. Portino, R. Volpini, S. Vittori, and
5
G. Cristalli
Dipartimento di Scienze Chimiche, University of Camerino, Camerino, Italy
5
In an attempt to improve the A2A selectivity of the 2-(aryl)alkylthio derivatives of adenosine, we
planned the synthesis of the corresponding derivatives of the 5’-N-ethylcarboxamidoadenosine (NECA).
For this purpose, we designed the synthesis of 2-mercapto-NECA to be pursued by means of an opening-
closure method. We obtained the open AICAR analog; however, ring closure efforts failed to give the
desired compound. The newly synthesized AICAR derivative could potentially be endowed with antiviral
or antitumoral activity.
INTRODUCTION
Derivatives of adenosine substituted at the C2 position of the purine ring with
(aryl)alkylthio groups have been reported to possess coronary vasodilating activity
and platelet aggregation inhibitory activity, probably due to their interaction with
the adenosine A2A receptors.[1–4]
In an attempt to improve the A2A selectivity of the 2-(aryl)alkylthio derivatives
of adenosine, since the substitution of the 4’-hydroxymethyl group with an N-
ethylcarboxamido substituent usually increased A2 vs. A1 binding affinity,[5–7] we
planned the synthesis of the corresponding derivatives of the 5’-N-ethylcarbox-
amidoadenosine (NECA).
In 1975, Kikugawa and Suehiro[8] reported the synthesis of 2-mercaptoadeno-
sine by the ‘‘opening-closure’’ method and its successive reaction with various 2-
(aryl)alkylbromides to obtain the corresponding 2-(aryl)alkylthio derivatives of
adenosine. Following a similar scheme, we designed the synthesis of 2-mercapto-
NECA, which could have been reacted with (aryl)alkylbromides to obtain the
desired compounds.
Supported by a grant from the Ministry of Research (FIRB RBAU 0019 ZEN) and by the University of
Camerino (Fondo di Ricerca di Ateneo).
Address correspondence to S. Vittori, Dipartimento di Scienze Chimiche, University of Camerino, via S.
Agostino 1, Camerino I-62032, Italy; E-mail: sauro.vittori@unicam.it
415
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416
S. Costanzi et al.
SCHEME 1 Preparation of AICAR analog 4.

S. Costanzi et al.
417
For this purpose, the 4’-hydroxymethyl group of the commercially available
2’-3’-isopropilideneadenosine was oxidized to carboxylic acid to obtain compound
1, which was reacted with m-chloroperbenzoic acid in order to form an N-oxide
at the N1 position of the purine ring (2). After deprotection of compound 2 by
treatment with HC1 in dioxane, the obtained compound 3 was refluxed with
NaOH to open the purine ring giving the AICAR analog 4 in low yield
1
(Scheme 1), whose identity has been confirmed by means of H-NMR spectros-
copy and mass spectrometry.
In order to confirm the structure of compound 4 and to overcome the
difficulties in handling carboxylic acids, compound 1 was converted to the
corresponding N-ethylcarboxamido derivative 5, which was then deprotected to
obtain NECA. The latter was treated with m-Cl-perbenzoic acid and the resulting N-
oxide derivative was refluxed with NaOH yielding compound 4 (Scheme 1).
The second route proved to be preferable both in terms of total yield and
easiness of handling.
In a search for an alternate and shorter synthetic route, an attempt to open
the isopropylidene protected nucleoside 2 resulted in the elimination of the 3’-
hydroxyl group and in the formation of a C3’-C4’-double bond (Scheme 2).
1
The structure of the obtained compound 8 has been confirmed by means of H-
NMR spectroscopy.
Compound 4 was treated with CS2 under different reaction conditions, in an
attempt to obtain a closed purine ring bearing a mercapto group at the C2 position.
The resulting compound would have been treated with ethylamine to give the
desired 2-mercapto derivative of NECA. However, these ring closure efforts failed
to give the desired compound.
In order to overcome these problems, we synthesized the wanted 2-(aryl)
alkylthio derivatives of NECA by reacting 2-iodoNECA with the appropriate
mercaptans, as reported elsewhere.[9]
In conclusion, the above described reactions yielded new AICAR analogs,
which will be tested for their antiviral and antitumor activity, and can constitute the
starting point for further modifications of AICAR.
SCHEME 2

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S. Costanzi et al.
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