Total synthesis and structural confirmation of chlorodysinosin A.
The first enantiocontrolled total synthesis of the marine sponge metabolite chlorodysinosin A is described. The structure and absolute configuration are identical to those of dysinosin A except for the presence of a novel 2S,3R-3-chloroleucine residue in the former. A concise stereocontrolled synthesis of the new chlorine-containing amino acid fragment was developed. An X-ray cocrystal structure of synthetic chlorodysinosin A with the enzyme thrombin confirms the structure and configuration assignment achieved through total synthesis. Within the aeruginosin family of natural products, chlorodysinosin A is the most potent inhibitor of the serine proteases thrombin, factor VIIa, and factor Xa, which are critical enzymes in the process leading to platelet aggregation and fibrin mesh formation in humans.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, C.P. 6128, Station Centre-ville, Montréal, P.Q., H3C 3J7 Canada.
Del Valle
Juan R
JR
Xue
Yafeng
Y
Blomberg
Niklas
N
D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000737:chemistry / Q000187:drug effects; D013237:Stereoisomerism; D013917:Thrombin / Q000737:chemistry
D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; C523036:chlorodysinosin A; C470588:dysinosin A; D012697:Serine Endopeptidases; D013917:Thrombin