Rearranging the bicyclo[3.1.0]hexane template of carbocyclic nucleosides to improve binding recognition by kinases

Article abstract of DOI:10.1080/15257770701490175

A novel bicyclo[3.1.0]hexane carbocyclic nucleoside (4) with a south-like conformation amenable to interact with the herpes thymidine kinase (HSV-tk) was synthesized with an endo-hydroxyl group positioned at the tip of the bicyclo[3.1.0]hexane ring system

Full text of DOI:10.1080/15257770701490175

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Rearranging The Bicyclo[3.1.0]Hexane
Template Of Carbocyclic Nucleosides To
Improve Binding Recognition By Kinases
Victor E. Marquez a & Maria J. Comin a
a Laboratory of Medicinal Chemistry, Center for Cancer Research ,
National Cancer Institute at Frederick , Frederick, Maryland, USA
Published online: 10 Dec 2007.
To cite this article: Victor E. Marquez & Maria J. Comin (2007) Rearranging The Bicyclo[3.1.0]Hexane
Template Of Carbocyclic Nucleosides To Improve Binding Recognition By Kinases, Nucleosides,
Nucleotides and Nucleic Acids, 26:6-7, 585-588, DOI: 10.1080/15257770701490175
To link to this article: http://dx.doi.org/10.1080/15257770701490175
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Nucleosides, Nucleotides, and Nucleic Acids, 26:585–588, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701490175
REARRANGING THE BICYCLO[3.1.0]HEXANE TEMPLATE OF
CARBOCYCLIC NUCLEOSIDES TO IMPROVE BINDING RECOGNITION
BY KINASES
Victor E. Marquez and Maria J. Comin
Laboratory of Medicinal Chemistry,
2
Center for Cancer Research, National Cancer Institute at Frederick, Frederick,
Maryland, USA
A novel bicyclo[3.1.0]hexane carbocyclic nucleoside (4) with a south-like conformation
2
amenable to interact with the herpes thymidine kinase (HSV-tk) was synthesized with an endo-
hydroxyl group positioned at the tip of the bicyclo[3.1.0]hexane ring system opposite to the tip of
the fused cyclopropane ring. The introduction of the hydroxymethyl chain through a Baylis-Hillman
type reaction and the regioselective opening of a cyclic sulfite intermediate to introduce the nitrogen
functionality at the correct position are highlighted.
Keywords Carbocyclic nucleosides; bicyclo[3.1.0]hexane; herpes thymidine kinase
INTRODUCTION
Carbocyclic nucleosides built on a bicyclo[3.1.0]hexane template have
provided important clues to differentiate the contrasting conformational
preferences between kinases and polymerases.[1−3] Albeit the binding pref-
erence of the various polymerases examined to date is consistent for a north
rigid template, the kinases’ preference for the antipodal south conforma-
tion is sensitive to additional conformational restrictions imposed by the bi-
cyclo[3.1.0]hexane system, such as a higher syn ←→ anti energy barrier, which
in the case of pyrimidine nucleosides forces the disposition of the base into
the syn range. Also, the critical presence and the stereochemistry of the 3ꢁ-
OH (nucleoside numbering) on the pseudoribose ring are important struc-
tural elements for recognition by kinases.
In the case of the south thymidine analogue (1), the preference for the
syn conformation diminishes its substrate affinity for the first phosphoryla-
tion step catalyzed by the herpes thymidine kinase (HSV-tk).[2]
The Intramural Research Program of the NIH and Center for Cancer Research, NCI-Frederick,
MD, USA, supported this research.
Address correspondence to Victor E. Marquez, Laboratory of Medicinal Chemistry, Center for Can-
cer Research, NCI at Frederick, NIH, Frederick, MD 21702. E-mail: marquezv@dc37a.nci.nih.gov
585

586
V. E. Marquez and M. J. Comin
Because the fusion of the cyclopropane ring adjacent to the nucleobase
is responsible for the syn preference, we sought to alleviate this problem
by repositioning the fused cyclopropane ring in 1 to the other end of the
molecule generating a new compound (2) that still maintained an intact
south-like conformation but with the thymine ring in the anti disposition
(Scheme 1A).
SCHEME 1
Because compound 2 was prone to undergo ring opening at room tem-
perature via a retro aldol reaction, compound 3 was synthesized instead
(Scheme 1B). A crystal structure of compound 3 indeed confirmed that
the conformation of the nucleobase was anti, and the phosphorylation ef-
ficiency for the first step catalyzed by HSV-tk more than doubled relative
to compound 1.[3] Unfortunately, the removal of the critical 3ꢁ-OH proved
to be fatal for the second phosphorylation step, also catalyzed by HSV-tk.
This result prompted us to remedy the lack of recognition by HSV-tk re-
sulting from the absence of the 3ꢁ-OH by relocating this critical group in a
similar endo disposition but from the opposite end of the pseudoboat ring
(compare 2 versus 4, Scheme 1) where it could engage in H-bonding in a
manner akin to that of 1. Molecular docking with HSV-tk confirmed that
this was possible and the synthesis of 4 is described herein.
SYNTHESIS
Thymidine analog 4 was synthesized through a linear approach in ex-
cellent yield from the carbocyclic amine 5. The pseudosugar ring was pre-
pared from known cyclopentenone 8[4] employing two key steps: (1) a

Bicyclo[3.1.0]hexane Template of Carbocyclic Nucleosides
587
SCHEME 2
Baylis-Hillman reaction[5] to assemble the 5ꢁ-hydroxymethyl side chain, and
(2) a regioselective opening of cyclic sulfite 6 to introduce the nitrogen sub-
stituent at the correct position[6] (Scheme 2).
Therefore, treatment of cyclopentenone 8 with formaldehyde in the
presence of imidazole in aqueous media gave the desired hydroxymethyl
cyclopentenone 7 in high yield (Scheme 3).[7]
After protection of the primary hydroxyl group as a benzoyl ester,
the ketone functionality was diastereoselectively reduced by treatment
with sodium borohydride in the presence of cerium salts in quantitative
yield. Radical deoxygenation of the corresponding xanthate under Barton
conditions[8] gave the desired compound 11. Racemization was observed
during this step. This result can be rationalized in terms of the two reso-
nance structures of the intermediate radical, which happen to be energet-
ically equivalent and enantiomeric. In order to further test our synthetic
approach, we decided to continue the synthesis with racemic compound
11. Thus, after cleavage of the ketal ring, the corresponding diol was cy-
clopropanated and then converted to the sulfite derivative that reacted with
sodium azide in dimethylformamide to yield a 5 to 1 diastereomeric mixture
SCHEME 3

588
V. E. Marquez and M. J. Comin
of azide-alcohols favoring the desired isomer 14 in 82% yield. With interme-
diate 14 at hand, synthesis of the final racemic nucleoside was straightfor-
ward as shown in Scheme 4.
SCHEME 4
A slightly different approach in order to avoid racemization during the
radical deoxygenation is currently underway. The new synthetic approach
and the biological studies will be published in due course.
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1. Marquez, V.E.; Ezzitouni, A.; Russ, P.; Siddiqui, M.A.; Ford, H.; Feldman, R.J.; Mitsuya, H.; George,
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carbocyclic AZT triphosphate analogues. J. Am. Chem. Soc. 1998, 120, 2780–2789.
2. Marquez, V.E.; Ben-Kasus, T.; Barchi, J.J. Jr, Green, K.M.; Nicklaus, M.C.; Agbaria, R. Experimental
and structural evidence that herpes 1 kinase and cellular DNA polymerase(s) discriminates on the
basis of sugar pucker. J. Am. Chem. Soc. 2004, 126, 543–543.
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