Synthesis of halogenated 9-(dihydroxycyclopent-4′-enyl) adenines and their inhibitory activities against S-Adenosylhomocysteine hydrolase

Article abstract of DOI:10.1081/NCN-120022686

Novel halovinyl analogues of neplanocin A without 4′-hydroxymethyl group were easily synthesized starting from D-ribose via cyclopentenone 5 as a key intermediate and their inhibitory activity against SAH hydrolase was assayed.

Full text of DOI:10.1081/NCN-120022686

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Synthesis of Halogenated 9-(Dihydroxycyclopent-4′-
enyl) Adenines and Their Inhibitory Activities Against
S-Adenosylhomocysteine Hydrolase
Lak Shin Jeong a e , Jae Gyu Park a , Won Jun Choi a , Hyung Ryong Moon a , Kang Man Lee a
,
Hea Ok Kim b , Hee-Doo Kim d , Moon Woo Chun c , Hea-Young Park a , Kilhyoun Kim a & Yhun
Y. Sheen a
a College of Pharmacy , Ewha Womans University , Seoul, Korea
b Division of Chemistry and Molecular Engineering
c College of Pharmacy , Seoul National University , Seoul, Korea
d College of Pharmacy , Sookmyung Women's University , Seoul, Korea
e College of Pharmacy , Ewha Womans University , 11-1 Seodaemun-gu, Daehyun-dong,
120-750, Seoul, South Korea
Published online: 31 Aug 2006.
To cite this article: Lak Shin Jeong , Jae Gyu Park , Won Jun Choi , Hyung Ryong Moon , Kang Man Lee , Hea Ok Kim ,
Hee-Doo Kim , Moon Woo Chun , Hea-Young Park , Kilhyoun Kim & Yhun Y. Sheen (2003) Synthesis of Halogenated 9-
(Dihydroxycyclopent-4′-enyl) Adenines and Their Inhibitory Activities Against S-Adenosylhomocysteine Hydrolase, Nucleosides,
Nucleotides and Nucleic Acids, 22:5-8, 919-921, DOI: 10.1081/NCN-120022686
To link to this article: http://dx.doi.org/10.1081/NCN-120022686
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 919–921, 2003
Synthesis of Halogenated 9-(Dihydroxycyclopent-40-enyl)
Adenines and Their Inhibitory Activities Against
S-Adenosylhomocysteine Hydrolase
1
1
1
Lak Shin Jeong,1, Jae Gyu Park, Won Jun Choi, Hyung Ryong Moon,
Kang Man Lee,1 Hea Ok Kim,2 Hee-Doo Kim,4 Moon Woo Chun,3
Hea-Young Park,1 Kilhyoun Kim,1 and Yhun Y. Sheen1
*
1College of Pharmacy, Ewha Womans University, Seoul, Korea
2Division of Chemistry and Molecular Engineering and
3College of Pharmacy, Seoul National University, Seoul, Korea
4College of Pharmacy, Sookmyung Women’s University, Seoul, Korea
ABSTRACT
Novel halovinyl analogues of neplanocin A without 40-hydroxymethyl group were
easily synthesized starting from d-ribose via cyclopentenone 5 as a key interme-
diate and their inhibitory activity against SAH hydrolase was assayed.
Key Words: S-Adenosylhomocysteine hydrolase; Halogenated 9-(dihydroxy-
cyclopent-40-enyl) adenines.
Neplanocin A[1] and aristeromycin,[2] both natural products, are potent inhibi-
tors of S-adenosylhomocysteine (SAH) hydrolase, which inhibit SAM (S-adenosyl-
methionine) methyltransferase[3] and exhibit interesting antiviral activities.[4] The
analogue of neplanocin A, being devoid of the 40-hydroxymethyl group, has also
*Correspondence: Lak Shin Jeong, College of Pharmacy, Ewha Womans University, 11-1
Seodaemun-gu, Daehyun-dong, 120-750 Seoul, South Korea; Fax: +82 23 277 2851; E-mail:
lakjeong@ewha.ac.kr.
919
DOI: 10.1081/NCN-120022686
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

920
Jeong et al.

Halogenated 9-(Dihydroxycyclopent-40-enyl) Adenines
921
been discovered as a potent SAH hydrolase inhibitor.[5] If the 30-hydroxyl group of
the halovinyl nucleosides 1–4 would be oxidized by NADþ like in neplanocin A, the
oxidized products, keto derivatives, might be able to act as good Michael acceptors,
resulting in formation of a covalent bond between the inhibitors and SAH hydrolase
via elimination of halogen after Michael addition reaction. Irreversible inhibition of
SAH hydrolase has been expected to exhibit potent antiviral activities. Based on
these findings and hypothesis, we report the syntheses of halovinyl nucleosides 1–4
and their inhibitory activity against SAH hydrolase.
Cyclopentenone 5 was efficiently synthesized from d-ribose according to the
method developed in our laboratory. As shown in Sch. 1, introduction of halogens
at vinyl position of 5 was accomplished by treatment with Cl2=pyridine, Br2=triethyl
amine, or I2=pyridine in 68–94% yield. Treatment of halovinyl compounds 6–8 with
sodium borohydride in the presence of CeCl3 afforded stereoselectively and regio-
selectively the reduced congeners 9–11, respectively. Protection of 11 as a TBDPS
ether followed by fluorination via metal-halogen exchange using n-BuLi and N-fluoro-
benzenesulfonimide and desilylation afforded fluoro cyclopentenol 14 in 69% yield.
Mesylation of compounds 9–11 and 14 followed by coupling of the resulting mesy-
lates with adenine in the presence of NaH or K2CO3 and 18-crown-6 afforded the
protected nucleosides 19–22, respectively. The final products 1–4 were obtained by
treatment with 10–30% aqueous CF3CO2H.
All synthesized compounds were assayed for SAH hydrolase inhibition. Among
them, fluoro compound 4 exhibited the most potent SAH hydrolase inhibition
(IC50 ¼ 7.67 mM). The larger the halo substituent, the poorer proved the SAH hydro-
lase inhibition.
ACKNOWLEDGMENT
This work was supported by Korea Research Foundation (KRF-2001-005-
F00022).
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