Design, synthesis, and in vitro evaluation of APIO analogue of neplanocin A

Article abstract of DOI:10.1081/NCN-120023014

A novel apio analogue of neplanocin A was efficiently synthesized from D-ribose via stereoselective aldol-retroaldol reaction for introducing hydroxymethyl group and RCM reaction for synthesizing carbocycle, and its inhibitory activity against SAH hydrola

Full text of DOI:10.1081/NCN-120023014

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Design, Synthesis, and In Vitro Evaluation of APIO
Analogue of Neplanocin A
Hyung Ryong Moon a , Sung Hee Kwon a , Jeong Ah Lee a , Byul Nae Yoo a , Hea Ok Kim b
Moon Woo Chun c , Hee-Doo Kim d , Joong Hyup Kim e & Lak Shin Jeong a f
a College of Pharmacy , Ewha Womans University , Seoul, Korea
,
b Division of Chemistry and Molecular Engineering , Seoul National University , Seoul, Korea
c College of Pharmacy , Seoul National University , Seoul, Korea
d College of Pharmacy , Sookmyung Women's University , Seoul, Korea
e Korea Institute of Science and Technology , Seoul, Korea
f College of Pharmacy , Ewha Womans University , 11-1 Seodaemun-gu, Daehyun-dong,
Seoul, 120-750, South Korea
Published online: 31 Aug 2006.
To cite this article: Hyung Ryong Moon , Sung Hee Kwon , Jeong Ah Lee , Byul Nae Yoo , Hea Ok Kim , Moon Woo Chun , Hee-
Doo Kim , Joong Hyup Kim & Lak Shin Jeong (2003) Design, Synthesis, and In Vitro Evaluation of APIO Analogue of Neplanocin
A, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 1475-1477, DOI: 10.1081/NCN-120023014
To link to this article: http://dx.doi.org/10.1081/NCN-120023014
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1475–1477, 2003
Design, Synthesis, and In Vitro Evaluation of APIO
Analogue of Neplanocin A
Hyung Ryong Moon,1 Sung Hee Kwon,1 Jeong Ah Lee,1 Byul Nae Yoo,1
Hea Ok Kim,2 Moon Woo Chun,3 Hee-Doo Kim,4 Joong Hyup Kim,5
and Lak Shin Jeong1,
*
1College of Pharmacy, Ewha Womans University, Seoul, Korea
2Division of Chemistry and Molecular Engineering
3
and College of Pharmacy, Seoul National University, Seoul, Korea
4College of Pharmacy, Sookmyung Women’s University, Seoul, Korea
5Korea Institute of Science and Technology, Seoul, Korea
ABSTRACT
A novel apio analogue of neplanocin A was efficiently synthesized from d-ribose
via stereoselective aldol-retroaldol reaction for introducing hydroxymethyl group
and RCM reaction for synthesizing carbocycle, and its inhibitory activity against
SAH hydrolase was assayed.
Key Words: Neplanocin A; Apio nucleosides; S-Adenosylhomocysteine
hydrolase.
S-adenosylhomocysteine (SAH) hydrolase catalyzes the hydrolysis of S-adeno-
sylhomocysteine to adenosine and homocysteine.[1] Inhibition of SAH hydrolase
accumulates S-adenosylhomocysteine in cell, which in turn interrupts the
*Correspondence: Lak Shin Jeong, College of Pharmacy, Ewha Womans University, 11-1
Seodaemun-gu, Daehyun-dong, Seoul 120-750, South Korea; Fax: +82 2 3277 2851;
E-mail: lakjeong@ewha.ac.kr.
1475
DOI: 10.1081/NCN-120023014
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1476
Moon et al.
Scheme 1. Reagentsa: a) i) acetone, c-H2SO4, ii) CH2CHMgBr; b) NaIO4; c) CH2O, K2CO3;
d) i) Ph3PCH3Br, KOt-Bu, ii) Grubbs catalyst (2nd Generation); e) i) TrCl, Pyridine, DMAP.
ii) MsCl, Et3N; f) adenine, K2CO3, 18-crown-6; g) 66% aqueous CF3CO2H.
transmethylation of viral mRNA via inhibition of SAM (S-adenosylmethionine)
methyltransferase, resulting in antiviral activities.[1] Nucleosides in which the fura-
nose ring oxygen and C20-methylene are transposed are called apio nucleosides.
Apio-ddA was reported to have anti-HIV activity comparable to that of the parent
ddA. On the basis of these findings, we report the synthesis and biological activity of
apio derivative of neplanocin A, which is one of potent inhibitors of SAH hydrolase,
expecting it to exhibit the inhibition of SAH hydrolase by tightly binding to the
enzyme.
d-Ribose was converted to the 2,3-acetonide under acidic condition, which was
treated with vinylmagnesium bromide to afford the allylic alcohol 2 stereoselectively
(Sch. 1).[2] Oxidative cleavage of the vicinal diol of allylic alcohol 2 using NaIO4
gave lactol 3, which was reacted with formaldehyde and potassium carbonate to
give 4 via recurrent aldol-retroaldol reaction, stereoselectively.[3] Wittig reaction
of 4 using triphenylphosphonium methyl ylide followed by RCM (ring-closing
metathesis)[4] of the resulting diene employing Grubbs catalyst (second generation)
produced cyclopentenol 5 in excellent yield. Protection of primary hydroxyl group
of 5 as a trityl ether and then mesylation of secondary hydroxyl group gave glycosyl
donor 6. Coupling of 6 with adenine in the presence of K2CO3 afforded the desired
N9 isomer 8 (61%) as a major product with concomitant formation of minor isomer
7 (9%). Assignments of isomers of N7 product and N9 product were accomplished
by comparison of UV data.[5] The final product 1 was obtained after concomitant
deprotection of trityl and isopropylidene groups of 8 under 66% aqueous trifluor-
oacetic acid.
The final product 7 didn’t show significant inhibition against SAH hydrolase,
maybe due to being impossible not only to bind to the enzyme tightly, but also
for NADþ to oxidize the tertiary hydroxyl group at C30-position.
ACKNOWLEDGMENT
This research was supported by the grant from Korea Research Foundation
(Grant KRF-2001-005-F00022).

APIO Analogue of Neplanocin A
1477
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