One-Pot Synthesis of α,γ-Dinucleoside 5′-Triphosphates, G5′pppG and A5′pppA, Using S,S′-Bis(4-chlorophenyl) phosphorodithioate

Abstract

S,S′-Bis(4-chlorophenyl) phosphorodithioate was useful for the synthesis of α,γ-dinucleoside 5′-triphosphates, G5′pppG and A5′pppA starting from the corresponding unprotected nucleoside 5′-phosphates under neutral conditions. G5′pppG was used for the synthesis of m7G5′pppG by means of the N7-methylation of one of two guanine moieties of G5′pppG.

MutT homologue 1 (MTH1) catalyzes the hydrolysis of mutagenic O6-methyl-dGTP

“…Methylations on nucleotides in DNA by MMS mostly result in N7-methylguanine (83%) ( 36 ) and only produce minor amounts of O6-methylguanine (0.3% of dN methylations). Based on this information and the fact that N7-methyl-dGTP has been described to be the major product formed after MMS or iodomethane treatment of dGTP ( 37 , 38 ), we successfully generated N7-methyl-dGTP using this route. The formation of N7-methylated dGTP from iodomethane methylation of dGTP was verified by NMR disclosing the presence of a large H8-proton shift arising when the methylation occurs at the N7 position ( 39 , 40 ) ( Supplementary Figure S3A and B ).…”

General Procedure for the Synthesis of Dinucleoside Polyphosphates

“…Most symmetrical and unsymmetrical dinucleoside 5′,5′-polyphosphates are prepared by reacting a nucleotide (the acceptor) with a 5′-activated nucleoside mono- or diphosphate (the donor). 5′-Morpholidates, , 5′-chloroquinolyl esters, 5′-pyrophosphorothioates, 5′-cyclosaligenyl phosphates, and phosphites , have all been used as donors. In each case, the prior preparation of an activating agent and/or the protection of the secondary hydroxyl or amino groups on the donor and/or isolation of the donor is required.…”

“…1 H NMR (D 2 O, 300 MHz): δ 4.04 (m, 10H, H 2 0 ,3 0 ,4 0 ,5 0 ), 5.77À5.88 (m, 3H, H 1 0 ,5C ), 5.94 (d, J = 7.4 Hz, 1H 5U ), 7.87 (t, J = 7.7 Hz, 2H, H 6 ). 13 P 1 ,P 3 -Diadenosine-5 0 -triphosphate, Trisodium Salt (11). 11,19c 5 0 -AMP free acid monohydrate (50 mg, 0.135 mmol) was used as the donor precursor.…”

“…677.12 [M + H] + , HRMS (TOF MS ES+) m/z = 677.1224, C 20 H 27 N 10 O 13 P 2 [M + H] + requires 677.1234.P 1 ,P 2 -Diguanosine-5 0 -diphosphate, Disodium Salt (7) 11. 5 0 -GMP disodium salt hydrate (54 mg, 0.135 mmol) was converted into its tri-n-butylammonium salt and used as the donor precursor and acceptor (1.5 equiv).…”