New neplanocin analogues. 12. Alternative synthesis and antimalarial effect of (6'R)-6'-C-methylneplanocin A, a potent AdoHcy hydrolase inhibitor.
An improved method for the synthesis of (6'R)-6'-C-methylneplanocin A (RMNPA, 2), a potent S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor, was developed via a chelation-controlled stereoselective addition of MeTiCl(3) to the neplanocin A 6'-aldehyde derivative 6. Compound 2 effectively inhibited the growth of malaria parasites both in vitro and in vivo. The antimalarial EC(50) value of 2 against Plasmodium berghei in mice was 1.0 mg/kg/day, which was superior to that of chloroquine (EC(50) = 1.8 mg/kg/day).
Shuto
Satoshi
S
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. matuda@pharm.hokudai.ac.jp
Minakawa
Noriaki
N
Niizuma
Satoshi
S
Kim
Hye-Sook
HS
Wataya
Yusuke
Y
Matsuda
Akira
A
D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects
D000962:Antimalarials; D004791:Enzyme Inhibitors; C075039:6'-C-methylneplanocin A; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine