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Impact of the Substituents on the Electronic Structure of the Four Most Stable Tautomers of Purine and Their Adenine Analogues.

ABSTRACT: Substituent effects at the C2-, C8-, and N-positions of adenine and purine on the structural and ?-electronic changes in their four tautomers were studied using the B97D3/aug-cc-pvdz computational level. The effect of various substituents (NO2, CN, CHO, Cl, F, H, Me, OMe, OH, and NH2) was characterized by the charge of the substituent active region (cSAR) approach and Hammett substituent constants ?. It has been found that for both adenine and purine derivatives, substituents from the C8-X position have a stronger influence on their electronic structure than from the C2-X and N-X positions. The presence of the amino group in adenine enhances the substituent effect compared to that which occurs in purine. In addition, its electronic structure is more sensitive to the effect of the substituent in 3H and 1H than in the 9H and 7H adenine tautomers. For a given substituent, a large variation in cSAR(X) values is observed, strongly dependent on the substitution position. For 7H and 9H adenine tautomers for C8-X systems, substituents reduce the aromaticity of the five-membered rings but increase the aromaticity of the six-membered rings.

SUBMITTER: Jezuita A

PROVIDER: S-EPMC7254788 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Impact of the Substituents on the Electronic Structure of the Four Most Stable Tautomers of Purine and Their Adenine Analogues.

Jezuita Anna A Szatylowicz Halina H Krygowski Tadeusz M TM

ACS omega 20200512 20

Substituent effects at the C2-, C8-, and N-positions of adenine and purine on the structural and π-electronic changes in their four tautomers were studied using the B97D3/aug-cc-pvdz computational level. The effect of various substituents (NO<sub>2</sub>, CN, CHO, Cl, F, H, Me, OMe, OH, and NH<sub>2</sub>) was characterized by the charge of the substituent active region (cSAR) approach and Hammett substituent constants σ. It has been found that for both adenine and purine derivatives, substituen ...[more]

PMID: 32478247

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Project description:Trichomonas vaginalis is a parasitic protozoan purine auxotroph possessing a unique purine salvage pathway consisting of a bacterial type purine nucleoside phosphorylase (PNP) and a purine nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition state mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a Km/Kd ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a Km/Kd ratio of 203,300. The tight binding of DADMe-ImmA supports a late SN1 transition state. Despite their tight binding to TvPNP, ImmA and DADMe-ImmA are weak inhibitors of human and P. falciparum PNPs. The crystal structures of the TvPNP x ImmA x PO4 and TvPNP x DADMe-ImmA x PO4 ternary complexes differ from previous structures with substrate analogues. The tight binding with DADMe-ImmA is in part due to a 2.7 A ionic interaction between a PO4 oxygen and the N1' cation of the hydroxypyrrolidine and is weaker in the TvPNP x ImmA x PO4 structure at 3.5 A. However, the TvPNP x ImmA x PO4 structure includes hydrogen bonds between the 2'-hydroxyl and the protein that are not present in TvPNP x DADMe-ImmA x PO4. These structures explain why DADMe-ImmA binds tighter than ImmA. Immucillin-H is a 12 nM inhibitor of TvPNP but a 56 pM inhibitor of human PNP. And this difference is explained by isotope-edited difference infrared spectroscopy with [6-18O]ImmH to establish that O6 is the keto tautomer in TvPNP x ImmH x PO4, causing an unfavorable leaving-group interaction.

Dataset Information

Impact of the Substituents on the Electronic Structure of the Four Most Stable Tautomers of Purine and Their Adenine Analogues.

Publications

Impact of the Substituents on the Electronic Structure of the Four Most Stable Tautomers of Purine and Their Adenine Analogues.

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