Prolinyl Phosphoramidates of Nucleotides with Increased Reactivity.

Autor: Humboldt A; Institute of Organic Chemistry, University of Stuttgart, 70569, Stuttgart, Germany., Rami F; Institute of Organic Chemistry, University of Stuttgart, 70569, Stuttgart, Germany., Topp FM; Institute of Organic Chemistry, University of Stuttgart, 70569, Stuttgart, Germany., Arnold D; Institute of Organic Chemistry, University of Stuttgart, 70569, Stuttgart, Germany., Göhringer D; Institute of Organic Chemistry, University of Stuttgart, 70569, Stuttgart, Germany., Pallan PS; Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee, 37232, USA., Egli M; Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee, 37232, USA., Richert C; Institute of Organic Chemistry, University of Stuttgart, 70569, Stuttgart, Germany.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Apr 08; Vol. 63 (15), pp. e202319958. Date of Electronic Publication: 2024 Feb 20.
DOI: 10.1002/anie.202319958
Abstrakt: Nucleoside monophosphates (NMPs) are the subunits of RNA. They are incorporated into growing complementary strands when sequences are copied in enzyme-free reactions using organic leaving groups at the phosphates. Amino acids are rarely considered as leaving groups, but proline can act as a leaving group when N-linked to NMPs, so that prolinyl NMPs hydrolyze in aqueous buffer at 37 °C, with half-life times as short as 2.4 h, and they act as monomers in enzyme-free primer extension. Still, their level of reactivity is insufficient for practical purposes, requiring months for some extensions. Herein we report the synthesis of eight substituted prolinyl AMPs together with seven related compounds and the results of a study of their reactivity. A δ-carboxy prolinyl NMP was found to be converted with a half-life time of just 11 min in magnesium-free buffer, and a δ-isopropyl prolinyl NMP was shown to react sevenfold faster than its prolinyl counterpart in enzyme-free genetic copying of RNA. Our results indicate that both anchimeric and steric effects can be employed to increase the reactivity of aminoacidyl nucleotides, i.e. compounds that combine two fundamental classes of biomolecules in one functional entity.
(© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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