Polyazacyclophanes Incorporating Two Pyridine Units and a Heteroaromatic Pendant Group as Potential Cleaving Agents of mRNA 5′-cap Structure

Abstract

Four hexaazacyclophanes, 16a-d, incorporating two pyridine units and a (pyridin-2-yl)methyl or (quinolin-2-yl)methyl pendant group at one of the ring N-atoms have been prepared. The key step of the synthesis is an intermolecular cyclization of N,N-bis{[6-(tosyloxymethyl)pyridin-2-yl]methyl}-2-nitrobenzenesulfonamide (7) with either tert-butyl bis{2-[(2-nitrophenylsulfonyl)amino]ethyl}carbamate (2a) or tert-butyl bis{3-[(2-nitrophenylsulfonyl)amino]propyl}carbamate (2b) in the presence of anhydrous Cs(2)CO(3). Removal of the acid-labile tert-butoxycarbonyl protection then allows attachment of the pendant group by reductive alkylation to the exposed secondary amino group, and deprotection of the remaining aliphatic ring N-atoms completes the synthesis. The ability of the cyclophanes and their dinuclear Cu(2+) and Zn(2+) complexes to cleave the mRNA cap structure, m(7)G(5')pppG(5') (1), has been studied.

Hydrolysis of dinucleoside phosphates – mRNA 5′ cap analogues – promoted by a binuclear copper(II)–zinc(II) complex

“…chemical agents that sequenceselectively cleave RNA molecules. The metal ion promoted hydrolytic reactions have been studied in more detail [15][16][17][18][19][20][21][22][23][24][25][26][27][28]. One aim of these works has been functional modelling of natural enzymes cleaving phosphoric anhydride bridges.…”