Multisubstrate adducts of the indole N-methyltransferase reaction have been designed in which a structural moiety representing the nucleophilic methyl acceptor is attached through the sulfur atom to the 5-(methylthio)adenosine and/or methionine moieties of the methyl donor, S-adenosyl-L-methionine. Indole derivatives attached through a 4-(3-indolyl)butyl sulfide or a 3-(3-indolyl)propyl sulfide linkage to 5'-thioadenosine or homocysteine have been synthesized, together with their corresponding methylsulfonium salts. These compounds have been assayed for their ability to inhibit rabbit lung indole N-methyltransferase. The adenosylsulfonium salts (5'-deoxyadenosyl)[4-(3-indolyl)but-1-yl]methylsulfonium perchlorate and (5'-deoxyadenosyl)[3-(3-indolyl)prop-1-yl]-methylsulfonium perchlorate were found to be inhibitors of this enzyme with Ki's of 12 and 44 microM, respectively. Neither of these compounds was effective in inhibiting the methylation of 3,4-dihydroxybenzoic acid, catalyzed by purified porcine catechol O-methyltransferase.
Several new analogues of adenosine bearing a lipophilic side chain at the 5'-position have been synthesized and investigated for their ability to inhibit histamine N-methyltransferase (HNMT). The 5'-deoxy-5'-[4-(3-indolyl)but-l-yl] thio}adenosine (2e), exhibited a pl 50 of 5.00 against guinea pig brain HNMT. Interestingly, the polar methyl sulphonium analogue (7c) was a more potent inhibitor of this enzyme (pl 50 =5.26). Both compounds were relatively ineffective inhibitors of rabbit adrenal phenylethanolamine N-methyltransferase (PNMT), rabbit lung indoleamine N-methyltransferase (INMT), and rat brain catechol O-methyltransferase (COMT). 5 -[N(4-phenylbutyl)] -amino-5 cieoxyadenosine (2a) and 5 -[N-methyl,N-(4-phenylbutyl] -amino-5 cleoxyadenosine (2b) also exhibited potent and selective inhibition against guinea pig brain HNMT. Results from kinetic studies indicate that the above compounds are inhibitors that compete for both the histamine and the S-adenosylmethionine (SAM) binding sites of HNMT. Compound lc is one of the most potent adenosine analogue inhibitors of HNMT known. Fig. 1: The histamine N-methyltransferase-catalyzed reaction.
2‐Acetamido‐3, 7‐dihydropyrrolo[2, 3‐d)pyrimidin‐4‐one reacts with dimethylamine and formaldehyde in glacial acetic acid to afford the two isomeric Mannich products, 2‐acetamido‐3, 7‐dihydro‐5‐dimethylamino‐methylpyrrolo[2, 3‐d]pyrimidin‐4‐one, and 2‐acetamido‐3, 7‐dihydro‐6‐dimethylaminomethylpyrrolo[2, 3‐d]‐pyrimidin‐4‐one, in a ratio of 3:1, respectively.
The S‐3‐(1‐methylindole)methyl and S‐3‐(1,2‐dimethylindole)methyl derivatives of 5′‐deoxy‐5′‐thioadenosine have been prepared by reaction of the appropriate 3‐indolemethylthioacetate with 5′‐deoxy‐5′‐chloro‐adenosine in basic media. 5′‐Deoxy‐5′‐(3‐indolemethylthio)adenosines unsubstituted at the indolic nitrogen, cannot be prepared via this route due to facile conversion of the precursor 3‐indolemethylthiol derivative to the corresponding 3,3′‐diindolemethyl sulfide.
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