Stereocontrolled synthesis of diene and enyne sugar-modified nucleosides and their interaction with S-adenosyl-L-homocysteine hydrolase

Article abstract of DOI:10.1081/NCN-120022634

Conjugated diene 5-7 and enyne 8 analogs derived from adenosine and uridine were synthesized employing Pd-catalyzed cross-coupling reactions.

Full text of DOI:10.1081/NCN-120022634

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Stereocontrolled Synthesis of Diene and Enyne Sugar-
Modified Nucleosides and Their Interaction with S-
Adenosyl-L-homocysteine Hydrolase
Stanislaw F. Wnuk a c , Pablo R. Sacasa a , Leigh N. Crain a , Elzbieta Lewandowska a , Jinsong
Zhang b & Ronald T. Borchardt b
a Department of Chemistry , Florida International University , Miami, Florida, USA
b Department of Pharmaceutical Chemistry , The University of Kansas , Lawrence, Kansas,
USA
c Department of Chemistry , Florida International University , University Park CP-307, Miami,
FL, 33199, USA
Published online: 31 Aug 2006.
To cite this article: Stanislaw F. Wnuk , Pablo R. Sacasa , Leigh N. Crain , Elzbieta Lewandowska , Jinsong Zhang & Ronald
T. Borchardt (2003) Stereocontrolled Synthesis of Diene and Enyne Sugar-Modified Nucleosides and Their Interaction
with S-Adenosyl-L-homocysteine Hydrolase, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 783-785, DOI: 10.1081/
NCN-120022634
To link to this article: http://dx.doi.org/10.1081/NCN-120022634
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 783–785, 2003
Stereocontrolled Synthesis of Diene and Enyne
Sugar-Modified Nucleosides and Their Interaction
with S-Adenosyl-L-homocysteine Hydrolase
1
1
Stanislaw F. Wnuk,1, Pablo R. Sacasa, Leigh N. Crain,
Elzbieta Lewandowska,1 Jinsong Zhang,2
and Ronald T. Borchardt2
*
1Department of Chemistry, Florida International University, Miami,
Florida, USA
2Department of Pharmaceutical Chemistry, The University of Kansas,
Lawrence, Kansas, USA
ABSTRACT
Conjugated diene 5–7 and enyne 8 analogs derived from adenosine and uridine
were synthesized employing Pd-catalyzed cross-coupling reactions.
Key Words: S-Adenosyl-l-homocysteine hydrolase; Coupling reactions; Enzyme
inhibitors; Nucleosides.
The cellular enzyme S-adenosyl-L-homocysteine hydrolase effects hydrolytic
cleavage of S-adenosyl-L-homocysteine, a potent inhibitor of crucial transmethyla-
tion enzymes, to adenosine and L-homocysteine.[1] Dienes 5 and 6 and enynes 8
derived from adenosine were designed as putative substrates of the ‘‘hydrolytic activ-
ity’’ of AdoHcy hydrolase.[2] Conceptually, enzyme-mediated addition of water
*Correspondence: Stanislaw F. Wnuk, Department of Chemistry, Florida International
University, University Park CP-307, 33199 Miami, FL, USA; Fax: +1 305 348 3772;
E-mail: wnuk@fiu.edu.
783
DOI: 10.1081/NCN-120022634
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

784
Wnuk et al.
might occur as a 1,2 or 1,4-process across the conjugated dienes=enynes resulting
in the generation of new species bearing hydroxyl, keto or acyl binding sites within
the enzymes.
Oxidation of the 20,30-O-isopropylideneadenosine and Wittig treatment of
the crude 50-aldehyde with Ph3P ¼ CHTs gave 60(E)-vinyl sulfone homonucleo-
sides 1. Stannyldesulfonylation (Bu3SnH=AIBN=toluene) of 1 yielded separable
mixtures of the vinyl 60(E and Z)-stannanes 2 and 3 (B ¼ A).[3] Stille coupling[4]
[(PPh3)4Pd=THF] of vinyl 60(E)-stannane 2 (B ¼ A) with ethyl (E)-3-iodopropenoate
and deacetonization (TFA=H2O) gave dienoic ester 5 (50E=70E, s-trans; 75%),
whereas reaction with ethyl (Z)-3-iodopropenoate gave the conjugated diene 6
(50E=70Z).[5] Analogous Pd-catalyzed coupling of 60(Z)-stannane derived from uri-
dine (3, B ¼ U) with ethyl (Z)-3-iodopropenoate and deacetonization afforded 7
(50Z=70Z; 68%).a
Dienoic esters 5 and 6 produced time- and concentration-dependent inactivation
of AdoHcy hydrolase with significant decreases in the enzyme’s NADþ content.
However, 5 and 6 upon incubation with the enzyme were not metabolized suggesting
that these dienes do not show ‘‘hydrolytic substrate activity’’.
Sonogashira coupling[4] [CuI=(PPh3)2PdCl2=Et2NH] of (E)-iodohomovinyl[3]
4
(B ¼ A) with (trimethylsilyl)acetylene gave enyne 8 (71%) with expected E-stereo-
chemistry. Enyne analogues (e.g., deprotected 8) with linear triple bond attach to
C60 would require a different vicinity for binding and=or addition of enzyme-bound
water and can be further modified at C80(X ¼ halogen, COOH).
aEthyl 1,5,6,7,8-Pentadeoxy-1-(uracil-1-yl)-b-D-ribo-non-5(Z),7(Z)-dienofuranuronate (7). For
general coupling and deprotection procedures see Ref.[5]: UV max 262 nm (e 37 700), min
223 nm (e 8 000); 1H NMR (Me2SO-d6) d 1.21 (t, J ¼ 7.1 Hz, 3, CH3), 3.88 (q, J ¼ 5.5 Hz,
1, H30), 4.08–4.16 (m, 3, H20 & CH2), 4.79 (dd, J ¼ 5.9, 8.8 Hz, 1, H40), 5.40 (d, J ¼ 6.0 Hz, 1,
OH30), 5.58 (d, J ¼ 5.6 Hz, 1, OH20), 5.66 (d, J ¼ 8.1 Hz, 1, H5), 5.76 (d, J ¼ 4.3 Hz, 1,
H10), 5.80 (d, J ¼ 11.5 Hz, 1, H80), 6.06 (dd, J ¼ 9.0, 11,2 Hz, 1, H50), 7.08 (‘‘t’’, J ¼ 11.7 Hz,
1, H70), 7.33 (‘‘t’’, J ¼ 11.5 Hz, 1, H60), 7.66 (d, J ¼ 8.1 Hz, 1, H6), 11.40 (br s, 1, NH); 13C
NMR (Me2SO-d6) d 14.98, 60.65, 73.68 & 75.00 (C20 & C30), 79.27 (C40), 90.35 (C10),
102.90 (C5), 120.13 (C80), 127.14 (C60), 138.40 & 139.47 (C50 & C6), 142.15 (C70),
151.45 (C2), 163.95 (C4), 166.35 (C90); MS (CI) m=z 339 (MHþ). Anal. Calcd for
C15H18N2O7 (338.33): C, 53.25; H, 5.36; N, 8.28. Found: C, 53.62; H, 5.61; N, 8.01.

Diene and Enzyme Sugar-Modified Nucleosides
ACKNOWLEDGMENTS
785
Supported by an award from the American Heart Association, Florida=Puerto
Rico Affiliate and MBRS RISE program R25 GM61347 (LNC).
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