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Two Scaffolds from Two Flips: (?,?)/(?,?) CH2/NH "Met-Im" Analogues of dTTP.

ABSTRACT: Novel ?,?-CH2 and ?,?-NH (1a) or ?,?-NH and ?,?-CH2 (1b) "Met-Im" dTTPs were synthesized via monodemethylation of triethyl-dimethyl phosphorimido-bisphosphonate synthons (4a, 4b), formed via a base-induced [1,3]-rearrangement of precursors (3a, 3b) in a reaction with dimethyl or diethyl phosphochloridate. Anomerization during final bromotrimethylsilane (BTMS) deprotection after Mitsunobu conjugation with dT was avoided by microwave conditions. 1a was 9-fold more potent in inhibiting DNA polymerase ?, attributed to an NH-group interaction with R183 in the active site.

SUBMITTER: Kadina AP

PROVIDER: S-EPMC4672865 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Two Scaffolds from Two Flips: (α,β)/(β,γ) CH2/NH "Met-Im" Analogues of dTTP.

Kadina Anastasia P AP Kashemirov Boris A BA Oertell Keriann K Batra Vinod K VK Wilson Samuel H SH Goodman Myron F MF McKenna Charles E CE

Organic letters 20150513 11

Novel α,β-CH2 and β,γ-NH (1a) or α,β-NH and β,γ-CH2 (1b) "Met-Im" dTTPs were synthesized via monodemethylation of triethyl-dimethyl phosphorimido-bisphosphonate synthons (4a, 4b), formed via a base-induced [1,3]-rearrangement of precursors (3a, 3b) in a reaction with dimethyl or diethyl phosphochloridate. Anomerization during final bromotrimethylsilane (BTMS) deprotection after Mitsunobu conjugation with dT was avoided by microwave conditions. 1a was 9-fold more potent in inhibiting DNA polymera ...[more]

PMID: 25970636

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Project description:BackgroundBiochemical equilibria are usually modeled iteratively: given one or a few fitted models, if there is a lack of fit or over fitting, a new model with additional or fewer parameters is then fitted, and the process is repeated. The problem with this approach is that different analysts can propose and select different models and thus extract different binding parameter estimates from the same data. An alternative is to first generate a comprehensive standardized list of plausible models, and to then fit them exhaustively, or semi-exhaustively.ResultsA framework is presented in which equilibriums are modeled as pairs (g, h) where g = 0 maps total reactant concentrations (system inputs) into free reactant concentrations (system states) which h then maps into expected values of measurements (system outputs). By letting dissociation constants Kd be either freely estimated, infinity, zero, or equal to other Kd, and by letting undamaged protein fractions be either freely estimated or 1, many g models are formed. A standard space of g models for ligand-induced protein dimerization equilibria is given. Coupled to an h model, the resulting (g, h) were fitted to dTTP induced R1 dimerization data (R1 is the large subunit of ribonucleotide reductase). Models with the fewest parameters were fitted first. Thereafter, upon fitting a batch, the next batch of models (with one more parameter) was fitted only if the current batch yielded a model that was better (based on the Akaike Information Criterion) than the best model in the previous batch (with one less parameter). Within batches models were fitted in parallel. This semi-exhaustive approach yielded the same best models as an exhaustive model space fit, but in approximately one-fifth the time.ConclusionComprehensive model space based biochemical equilibrium model selection methods are realizable. Their significance to systems biology as mappings of data into mathematical models warrants their development.

Dataset Information

Two Scaffolds from Two Flips: (?,?)/(?,?) CH2/NH "Met-Im" Analogues of dTTP.

Publications

Two Scaffolds from Two Flips: (α,β)/(β,γ) CH2/NH "Met-Im" Analogues of dTTP.

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