72360-76-0Relevant academic research and scientific papers
Exploring tryptamine conjugates as pronucleotides of phosphate-modified 7-methylguanine nucleotides targeting cap-dependent translation
Baran, Natalia,Golojuch, Sebastian,Jemielity, Jacek,Kasprzyk, Renata,Kopcial, Michal,Kowalska, Joanna,Sikorski, Pawel J.,Strzelecka, Dominika
, (2020)
Eukaryotic translation initiation factor 4E (eIF4E) is overexpressed in many cancers deregulating translational control of the cell cycle. mRNA 5′ cap analogs targeting eIF4E are small molecules with the potential to counteract elevated levels of eIF4E in cancer cells. However, the practical utility of typical cap analogs is limited because of their reduced cell membrane permeability. Transforming the active analogs into their pronucleotide derivatives is a promising approach to overcome this obstacle. 7-Benzylguanosine monophosphate (bn7GMP) is a cap analog that has been successfully transformed into a cell-penetrating pronucleotide by conjugation of the phosphate moiety with tryptamine. In this work, we explored whether a similar strategy is applicable to other cap analogs, particularly phosphate-modified 7-methylguanine nucleotides. We report the synthesis of six new tryptamine conjugates containing N7-methylguanosine mono- and diphosphate and their analogs modified with thiophosphate moiety. These new potential pronucleotides and the expected products of their activation were characterized by biophysical and biochemical methods to determine their affinity towards eIF4E, their ability to inhibit translation in vitro, their susceptibility to enzymatic degradation and their turnover in cell extract. The results suggest that compounds containing the thiophosphate moiety may act as pronucleotides that release low but sustainable concentrations of 7-methylguanosine 5′-phosphorothioate (m7GMPS), which is a translation inhibitor with in vitro potency higher than bn7GMP.
Reactivity Effects on Site Selectivity in Nucleoside Aralkylation: A Model for the Factors Influencing the Sites of Carcinogen-Nucleic Acid Interactions
Moschel, Robert C.,Hudgins, W. Robert,Dipple, Anthony
, p. 4180 - 4185 (2007/10/02)
Product distributions are described for 15 reactions between guanosine (1) and a series of p-Y-benzyl bromides (2a-e), p-Y-benzoyl chlorides (3a-e), and N-nitroso-N-(p-Y-benzyl)ureas (4a-e) where Y = a, O2N; b, Cl; c, H; d, CH3; e, CH3O.The yields of products from reaction at the 7-position of guanosine to produce 7-(p-Y-benzyl)guanosines (5a-e), at N2 to produce N2-(p-Y-benzyl)guanosines (6a-e), at the O6-position to produce O6-(p-Y-benzyl)guanosines (7a-e), and at the 5-position to produce 4-(p-Y-benzyl)-5-guanidino-1-β-D-ribofuranosylimidazoles (8a-e) arecorrelated with the mechanism of the reaction (i.e., the SN2 or SN1 character) imposed by the para substituent and/or leaving group and the nature of the incipient charge density (i.e., the "hardness" or "softness") at the reaction center.These observations, coupled with the literature on sites of reaction of carcinogens with nucleic acid components, are used to rationalize the site selectivity differences exhibited by the alkylating and aralkylating classes of carcinogens in their nucleic acid reactions.
