Nucleic acid related compounds. 6. Sugar-modified N<sup>6</sup>-(3-methyl-2-butenyl)adenosine derivatives, N<sup>6</sup>-benzyl analogs, and cytokinin-related nucleosides containing sulfur or formycin

Robins, Morris J.; Trip, Everard M.

doi:10.1021/bi00736a001

Cited by 42 publications

(25 citation statements)

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“…2′-Amino-2′-deoxy-3′,5′-O-(1,1,3,3-tetraisopropylsiloxane-1,3-diyl)adenosine (3) and N 6 -(3-methyl-2-butenyl)-adenosine were synthesized as described. 30,45 Protection of Hydroxy Acids. Hydroxybenzoic acids were protected via acetylation as described 27 in 80-95% yields, and the structures were verified by 1 H NMR.…”

Section: Methodsmentioning

confidence: 99%

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Selective Tight Binding Inhibitors of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase via Structure-Based Drug Design

et al. 1998

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the sleeping sickness parasite Trypanosoma brucei is a rational target for anti-trypanosomatid drug design because glycolysis provides virtually all of the energy for the bloodstream form of this parasite. Glycolysis is also an important source of energy for other pathogenic parasites including Trypanosoma cruzi and Leishmania mexicana. The current study is a continuation of our efforts to use the X-ray structures of T. brucei and L. mexicana GAPDHs containing bound NAD + to design adenosine analogues that bind tightly to the enzyme pocket that accommodates the adenosyl moiety of NAD + . The goal was to improve the affinity, selectivity, and solubility of previously reported 2′-deoxy-2′-(3-methoxybenzamido)adenosine (1). It was found that introduction of hydroxyl functions on the benzamido ring increases solubility without significantly affecting enzyme inhibition. Modifications at the previously unexploited N 6 -position of the purine not only lead to a substantial increase in inhibitor potency but are also compatible with the 2′-benzamido moiety of the sugar. For N 6 -substituted adenosines, two successive rounds of modeling and screening provided a 330-fold gain in affinity versus that of adenosine. The combination of N 6 -and 2′-substitutions produced significantly improved inhibitors. N 6 -Benzyl (9a) and N 6 -2-methylbenzyl (9b) derivatives of 1 display IC 50 values against L. mexicana GAPDH of 16 and 4 µM, respectively (3100-and 12500-fold more potent than adenosine). The adenosine analogues did not inhibit human GAPDH. These studies underscore the usefulness of structurebased drug design for generating potent and species-selective enzyme inhibitors of medicinal importance starting from a weakly binding lead compound.

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Section: Methodsmentioning

confidence: 99%

“…30 2-Methoxy-, 2,5-dimethyl-, and 2,3-dimethylbenzyl bromides were prepared from the corresponding alcohols using PBr 3 ; 31 2,3-dimethylbenzyl alcohol was made via LiAlH 4 reduction of the respective benzoic acid. 32 …”

Section: Chemistrymentioning

confidence: 99%

Selective Tight Binding Inhibitors of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase via Structure-Based Drug Design

et al. 1998

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“…The same conclusion was reached from the fact that gibberellic acid was found not to reverse the growth inhibitory (12,13), most growth inhibitory analogs (15)(16)(17) were found to have a more general function when evaluated at a given concentration for reversal of inhibition by added cytokinin and for correlation of inhibitory activity with structural features usually associated with cytokinin-active species (14).…”

Section: Methodsmentioning

confidence: 72%

“…The product was purified by chromatography on 30 g of Sephadex LH-20, elution with H20 and then with increasing concentrations of ethanol. The (15,200).…”

Section: Methodsmentioning

confidence: 99%

“…The successful preparation of a class of antagonists suggested that additional heterocyclic series of anticytokinins should exist. Several potentially inhibitory analogs have been prepared (15)(16)(17), but none of these fulfilled the criteria for anticytokinin activity to nearly the same extent as the original class of anticytokinins (14). The present report describes a new class of potential cytokinin antagonists, the activity of which is consistent with the criteria specified for anticytokinins.…”

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Anticytokinin activity of substituted pyrrolo[2,3- d ]pyrimidines

Skoog

Schmitz²,

Hecht³

et al. 1975

Proc. Natl. Acad. Sci. U.S.A.

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Ten substituted pyrrolo[2,3-dpyrimidines were tested as cytokinins and anticytokinins in the tobacco bioassay. Eight new anticytokinins were identified and two were found to be highly active. The most potent species were 4-cyclohexylamino-and 4-cyclopentylamino-2-methylthiopyrrolo[2,3-djpyrimidine, of which 0.05 and 0.009 AM concentrations, respectively, were required to produce detectable inhibition of the growth of tobacco callus cultured on a medium containing 0.003 uM 6(3-methyl-2-butenylamino)purine. The inhibition of growth by moderate (<6.6 uM) concentrations of these compounds was reversible by equal or higher concentrations of 6-(3-methyl-2-butenylamino)purine, but not by indole-3-acetic acid or gibberellic acid. These substituted pyrrolo[2,3-djpyrimidines were also found to enhance bud formation at high cytokinin concentrations, suggesting that a cytokinin may act at more than one cellular site in exerting its growth-promoting and morphogenetic effects.Cytokinins are a class of hormones which promote cell division and participate in the regulation of growth and morphogenesis in plants (1). Although all plants are thought to require cytokinins for growth, intact plants generally grow without exogenous cytokinins, presumably because they make their own. In fact, several highly active cytokinins have been found to occur naturally as N6-substituted adenine derivatives at the purine, ribonucleoside, and ribonucleotide levels (1). Cytokinins are also present in the transfer RNA's of most forms of life, although their presence in tRNA has not been shown to be related to their regulation of growth (1, 2).Cytokinins have been found to influence the behavior of mammalian cells. They have been reported, for example, to inhibit platelet aggregation (3) and the growth of several mammalian cell lines, including cancerous lines (4-6 and references in 5). N6-(3-Methyl-2-butenyl)adenosine (i6Ado) has been reported to be an immunosuppressive agent (7) and to induce hematological remissions in leukemia patients (8,9). Several cytokinins, including i6Ado, have also been shown to be capable of regulating the growth of phytohemagglutinin-transformed human lymphocytes (10 and references therein), presumably by involvement in cyclic AMP metabolism, and i6Ado was shown to act as a competitive inhibitor of beef heart cyclic AMP phosphodiesterase (11).To facilitate the study of the mechanism of cytokinin action and provide potential chemotherapeutic agents, we designed and synthesized a class of structural analogs of cytokinins which behave as anticytokinins in plant bioassays (12,13). Proof that these "anticytokinins" act at the same cellular sites as the cytokinins is not presently accessible, since cytokinin-anticytokinin interaction is not monitored at the molecular level, but this interpretation has been proposed on the basis of the observed biological activities of the analogs in several assays and on the close structural relationship between cytokinins and anticytokinins (14). The successful preparation of a class...

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References

1996

Chemistry of Heterocyclic Compounds: A Series of Monographs

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Nucleic acid related compounds. 6. Sugar-modified N⁶-(3-methyl-2-butenyl)adenosine derivatives, N⁶-benzyl analogs, and cytokinin-related nucleosides containing sulfur or formycin

Cited by 42 publications

References 38 publications

Selective Tight Binding Inhibitors of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase via Structure-Based Drug Design

Selective Tight Binding Inhibitors of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase via Structure-Based Drug Design

Anticytokinin activity of substituted pyrrolo[2,3- d ]pyrimidines

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Nucleic acid related compounds. 6. Sugar-modified N6-(3-methyl-2-butenyl)adenosine derivatives, N6-benzyl analogs, and cytokinin-related nucleosides containing sulfur or formycin

Cited by 42 publications

References 38 publications

Selective Tight Binding Inhibitors of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase via Structure-Based Drug Design

Selective Tight Binding Inhibitors of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase via Structure-Based Drug Design

Anticytokinin activity of substituted pyrrolo[2,3- d ]pyrimidines

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Nucleic acid related compounds. 6. Sugar-modified N⁶-(3-methyl-2-butenyl)adenosine derivatives, N⁶-benzyl analogs, and cytokinin-related nucleosides containing sulfur or formycin