Inhibition of Vaccinia RNA Guanine 7‐Methyltransferase by Compounds Designed as Multisubstrate Adducts

Structure-Based Design, Synthesis, and in vitro Evaluation of Bisubstrate Inhibitors for CatecholO-Methyltransferase (COMT)

“…The suspension was left in the refrigerator at 4 8C overnight, then the white precipitate was filtered off and washed with THF (5 mL 6-Amino-2-sulfanyl-3,4-dihydropyrimidin-4-one (19): [36] Thiourea (4.56 g, 60.00 mmol) and ethyl cyanoacetate (6.40 mL, 60.00 mmol) were added to EtONa (4.29 g, 63.00 mmol) in EtOH (44 mL), and the mixture was heated to reflux for 2 h. The formed precipitate was filtered off, and the solvents were evaporated in vacuo. The resulting solid residue and the initial precipitate were dissolved in H 2 O (50 mL), then HOAc was added until complete precipitation of 19 as a white powder (8.00 g, 93 % (20): [37] An aqueous suspension of Ra-Ni (12.00 g) was added to a vigorously stirred mixture of 19 N-(6-Oxo-1,6-dihydropyrimidin-4-yl)benzamide (18). A mixture of 20 (0.61 g, 5.47 mmol) and benzoic anhydride (2.96 g, 13.08 mmol) was heated to 140 8C.…”

“…[13±15] Bisubstrate inhibitors of enzymes such as spermidine synthase, [16] farnesyl transferase, [17] vaccinia RNA guanine 7-methyltransferase, [18] and indole Nmethyltransferase [19] have been shown to display, in many cases, higher affinities than inhibitors mimicking only one substrate. However, no lead structure for a bisubstrate inhibitor of COMT has been reported.…”

The Lives of Malus and His Bicentennial Law

“…Through mechanism‐based considerations, SAM–nucleotide adducts, which mimic a transition state structure of (guanine‐N7) methylation, have been at the basis for the design of novel molecules of potentially chemotherapeutic interest. Thus, more than 20 years ago, Benghiat et al designed several multi‐substrate adducts and evaluated their antiviral effects on the vaccinia virus N7‐MTase 31. This study led to the identification of 5′‐deoxy‐5′ (6‐(2‐aminopyrrolo(2,3‐d)‐pyrimidine‐4‐one)methylthio)adenosine (dAPPMA) as a potent antiviral reagent (IC 50 = 92 µM).…”

Synthesis of Adenine Dinucleosides 2′,5′‐Bridged by Sulfur‐Containing Linkers as Bisubstrate SAM Analogues for Viral RNA 2′‐O‐Methyltransferases

“…Particularly, Arimondo developed transition state analogues of DNA methylation based on the coupling of cytosine analogues to adenosine to give 5‐methylcytosine‐adenosine compounds . Moreover, the first bisubstrates targeting RNA methyltransferases have been described in 1986 and one compound designed with the SAM moiety linked to the C6 of a guanine derivative demonstrated an inhibitory activity against vaccinia RNA N 7‐guanine MTase for the N 7‐methylation of the 5′‐cap structure . More recently, in the context of deciphering the roles of N 6m‐A RNA modifications and consequently exploring the functions of N 6‐A RNA MTases, SAM‐adenosine conjugates mimicking the transition state of methylation at N 6 were synthesized by connecting a SAM analogue to the N 6‐position of an adenosine unit via alkyl and urea linkers .…”