Synthesis of 5'-methylenearisteromycin and its 2-fluoro derivative with potent antimalarial activity due to inhibition of the parasite S-adenosylhomocysteine hydrolase.
5'-methylenearisteromycin 5 and its 2-fluoro derivative 6, which were designed as antimalarial agents because of their AdoHcy hydrolase inhibition, were synthesized from D-ribose, using a stereoselective intramolecular radical cyclization as the key step to construct the carbocyclic structure. These compounds were evaluated as AdoHcy hydrolase inhibitors with the recombinant human and malarial parasite enzymes. Although 5 and 6 were both potent inhibitors of the malarial parasite AdoHcy hydrolase, the 2-fluoro derivative 6 proved to be superior due to its lower inhibitory effect on the human enzyme. In addition, 6 was identified as a potent antimalarial agent using an in vitro assay system with Plasmodium falciparum.
Takagi
Chieko
C
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
Sukeda
Makoto
M
Kim
Hye-Sook
HS
Wataya
Yusuke
Y
Yabe
Saori
S
Kitade
Yukio
Y
Matsuda
Akira
A
Shuto
Satoshi
S
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D016339:Spectrometry, Mass, Fast Atom Bombardment
C511504:5'-methylenearisteromycin; D000962:Antimalarials; D043383:Adenosylhomocysteinase; D000241:Adenosine