Abstract:A direct method for the preparation of 5'-S-alkynyl-5'-thioadenosine and 5'-S-allenyl-5'-thioadenosine has been developed. Treatment of a protected 5'-acetylthio-5'-deoxyadenosine with sodium methoxide and propargyl bromide followed by deprotection gave the 5'-S-propargyl-5'-thioadenosine 4. Under controlled base-catalysis with sodium tert-butoxide in tert-butyl alcohol 4 was quantitatively converted into 5'-S-allenyl-5'-thioadenosine 5 or 5'-S-propynyl-5'-thioadenosine 6. Incubation of recombinant human place… Show more
“…[152] However, similarly to cytallene and adenallene, the allenic thioether 141 is active against the vaccinia virus and was prepared by basic isomerization of the corresponding propargylic thioether. [153] …”
Nowadays, about 150 natural products comprising an allenic or cumulenic structure are known. The chemistry of these compounds has turned out to be a very attractive and prolific area of interest: advances in the isolation and characterization of new allenic natural products have led to the establishment of efficient synthetic procedures which in many cases also open up an access to enantiomerically pure target molecules. Inspired by the intriguing biological activities of many allenic natural products, allene moieties are now systematically introduced in pharmacologically active classes of compounds (steroids, prostaglandins, amino acids, nucleosides). The functionalized allenes thus obtained often exhibit impressive activities as mechanism-based enzyme inhibitors, cytotoxic, or antiviral agents. A prerequisite for further developments in this field is the efficient stereoselective synthesis of allene derivatives.
“…[152] However, similarly to cytallene and adenallene, the allenic thioether 141 is active against the vaccinia virus and was prepared by basic isomerization of the corresponding propargylic thioether. [153] …”
Nowadays, about 150 natural products comprising an allenic or cumulenic structure are known. The chemistry of these compounds has turned out to be a very attractive and prolific area of interest: advances in the isolation and characterization of new allenic natural products have led to the establishment of efficient synthetic procedures which in many cases also open up an access to enantiomerically pure target molecules. Inspired by the intriguing biological activities of many allenic natural products, allene moieties are now systematically introduced in pharmacologically active classes of compounds (steroids, prostaglandins, amino acids, nucleosides). The functionalized allenes thus obtained often exhibit impressive activities as mechanism-based enzyme inhibitors, cytotoxic, or antiviral agents. A prerequisite for further developments in this field is the efficient stereoselective synthesis of allene derivatives.
“…The enzyme is of considerable interest for questions of the coupling between catalytic function and protein motion, since its large domain−domain oscillation in the free state is completely arrested during the catalytic cycle (the domain structure of the monomeric subunit of the homotetrameric enzyme is shown in Figure ). In addition, AdoHcy hydrolase is considered a drug target for the therapy of viral ( , ) and parasitic infections (), as well as cardiovascular conditions (). 1 The domain structure of human AdoHcy hydrolase (), shown for a monomeric subunit of the homotetrameric enzyme.…”
Residues glutamate 156 (E156), aspartate 190 (D190), asparagine 181 (N181), lysine 186 (K186), and asparagine 191 (N191) in the active site of S-adenosylhomocysteine (AdoHcy) hydrolase have been mutated to alanine (A). AdoHcy hydrolase achieves catalysis of AdoHcy hydrolysis to adenosine (Ado) and homocysteine (Hcy) by means of a redox partial reaction (3'-oxidation of AdoHcy at the beginning and 3'-reduction of Ado at the end of the catalytic cycle) spanning an elimination/addition partial reaction (elimination of Hcy from the oxidized substrate and addition of water to generate the oxidized product), with the enzyme in an open NAD(+) form in the ligand-free state and in a closed NADH form during the elimination/addition partial reaction. Mutation K186A reduces the rate of a model enzymatic reaction for the redox partial reaction by a factor of 280000 and the rate of a model reaction for the elimination/addition partial reaction by a factor of 24000, consistent with a primary catalytic role in both partial reactions as a proton donor/acceptor at the 3'-OH/3'-keto center. Secondary roles for N181 and N191 in localizing the flexible side chain of K186 in a catalytically effective position are supported by rate reduction factors for N181A of 2500 (redox) and 240 (elimination/addition) and for N191A of 730 (redox) and 340 (elimination/addition). A role of D190 in orienting the substrate for effective transition-state stabilization is consistent with rate reduction factors of 1300 (redox) and 30 (elimination/addition) for D190A. Residue E156 may act to maintain K186 in the desired protonation state: rate deduction factors are 1100 (redox) and 70 (elimination/addition). The mutational increases in free energy barriers for k(cat)/K(M) are described by a linear combination of the effects for the partial reactions with the coefficients equal to the fractional degree that each partial reaction determines the rate for k(cat)/K(M). A similar linear equation for k(cat) overestimates the barrier increase by a uniform 5 kJ/mol, probably reflecting reactant-state stabilization by the wild-type enzyme that is abolished by the mutations.
“…Covalent inhibition of AdoHcy hydrolase with 5‘-deoxy-5‘-difluoromethylthioadenosine by the electrophilic entity (thioformyl fluoride) liberated from the substrate has been reported by Guillerm and co-workers. 11a,b They also developed a new series of the 5‘-thioadenosine analogues substituted at sulfur with allenyl and propynyl groups that are processed by hydrolytic activity of the enzyme causing its irreversible inactivation 11c. The X-ray crystal structures of AdoHcy hydrolase revealed an unusual dual role for a catalytic water molecule at the active site …”
Moffatt oxidation of 2',3'-O-isopropylideneuridine (1a) and treatment of the crude 5'-aldehyde with formylmethylene-stabilized Wittig reagent gave the vinylogously extended 7'-aldehyde2a. Condensation of 2a with ethoxycarbonyl- or dibromomethylene phosphorane reagents gave the conjugated dienes 6a and 4a, respectively. Deacetonization gave diene ester 7a [5'(E),7'(E); with s-trans conformation] and dibromodiene 5a [5'(E)], respectively. Analogously, 2',3'-O-isopropylideneadenosine (1b) was Wittig-extended into the conjugated dibromodiene 5b [5'(E)] and dienoic ester 7b [5'(E),7'(E)]. Furthermore, palladium-catalyzed coupling of the vinyl 6'(E)-stannanes 14 with (E) and (Z) ethyl 3-iodoacrylate gave stereodefined access to dienoic esters 7 (E,E) and 16 (E,Z). Incubation of AdoHcy hydrolase with 100 microM of 5b resulted in partial inhibition of the enzyme without any apparent change in the enzyme's nicotinamide adenine dinucleoside (NAD(+)) content. In contrast, 7b and 16b produced time- and concentration-dependent inactivation of S-adenosyl-L-homocysteine (AdoHcy) hydrolase producing significant decreases in the enzyme's NAD(+) content. However, 7b and 16b upon incubation with AdoHcy hydrolase were not metabolized suggesting that these compounds are type I mechanism-based inhibitors. No specific antiviral activity was noted for 5a,b, 7a,b, and 16a,b against any of the viruses tested; dibromodiene 5b proved cytotoxic at a concentration > or =6.7 microM and cytostatic at > or =11 microM, while dienoic esters 16a,b showed activity against both varicella-zoster virus (at 10 microM, 16a) and cytomegalovirus (at 10 microM, 16a; 18 microM, 16b).
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