Diadenosine and Diuridine Poly(borano)phosphate Analogues: Synthesis, Chemical and Enzymatic Stability, and Activity at P2Y<sub>1</sub> and P2Y<sub>2</sub> Receptors
Bibliographic record
Abstract
Dinucleoside polyphosphates, NpnN', exert their physiological effects via P2 receptors. They are attractive drug targets as they offer better stability and specificity compared to nucleotides, the most common P2-receptor ligands. To further improve the properties of NpnN', which are still pharmacologically unsatisfactory, we developed novel boranophosphate isosteres of dinucleoside polyphosphates, denoted as Npn(B)N. These analogues were obtained in a facile and efficient synthesis as the exclusive products in a concerted reaction of two nucleoside phosphorimidazolides and inorganic boranophosphate. This unusual reaction is due to the preorganization of three reactant molecules by the Mg2+ ion. We found that Ap3/5(beta/gamma-B)A analogues were potent P2Y1-R agonists. Ap5(gamma-B)A was equipotent to 2-MeS-ADP (EC50 6.3x10(-8) M), thus making it one of the most potent P2Y1-R agonists currently known. Moreover, Ap5(gamma-B)A did not activate P2Y2-R. In contrast, Up3/5(beta/gamma-B)U analogues were extremely poor agonists of both P2Y1-R and P2Y2-R. Npn(B)N analogues exhibited remarkable chemical stability under physiological conditions. Under conditions mimicking gastric juice, Np3(beta-B)N analogues exhibited a half-life (t1/2) of 1.3 h, whereas Np5(gamma-B)N degraded at a much faster rate (t1/2 18 min). The hydrolysis of Ap3(beta-B)A by human nucleotide pyrophosphatase phosphodiesterases (NPP1 and NPP3) was slowed by 40% and 59%, respectively, as compared to Ap3A. However, this effect of the boranophosphate was position-dependent, as Np5(gamma-B)N was degraded at a rate comparable to that of Np5N. In summary, Ap5(gamma-B)A appears to be a highly potent and selective P2Y1-R agonist, as compared to the parent compound. This promising scaffold will be applied in the design of future metabolically stable analogues.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".