A Simple New Synthesis of 2‐Thiopyrimidine Nucleosides

Vorbrüggen, Helmut; Strehlke, P.; Schulz, Günter

doi:10.1002/anie.196909762

Cited by 11 publications

(7 citation statements)

References 10 publications

(2 reference statements)

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“…For the 2-thio-dT-CE-phosphoramidite ( 3 ), some syntheses are described (54,55), the yields of which, however, are unsatisfying, as several structural isomers are formed during the nucleosidation reaction (56,57). To circumvent these problems, we developed a novel strategy by protecting the 2-thiothymine ( 8 ) as a thioether ( 9 ) with a para -acetoxybenzyl group (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Pseudo-complementary PNA actuators as reversible switches in dynamic DNA nanotechnology

Ackermann

Famulok

2013

Nucleic Acids Research

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The structural reorganization of nanoscale DNA architectures is a fundamental aspect in dynamic DNA nanotechnology. Commonly, DNA nanoarchitectures are reorganized by means of toehold-expanded DNA sequences in a strand exchange process. Here we describe an unprecedented, toehold-free switching process that relies on pseudo-complementary peptide nucleic acid (pcPNA) by using a mechanism that involves double-strand invasion. The usefulness of this approach is demonstrated by application of these peptide nucleic acids (PNAs) as switches in a DNA rotaxane architecture. The monomers required for generating the pcPNA were obtained by an improved synthesis strategy and were incorporated into a PNA actuator sequence as well as into a short DNA strand that subsequently was integrated into the rotaxane architecture. Alternate addition of a DNA and PNA actuator sequence allowed the multiple reversible switching between a mobile rotaxane macrocycle and a stationary pseudorotaxane state. The switching occurs in an isothermal process at room temperature and is nearly quantitative in each switching step. pcPNAs can potentially be combined with light- and toehold-based switches, thus broadening the toolbox of orthogonal switching approaches for DNA architectures that open up new avenues in dynamic DNA nanotechnology.

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Section: Resultsmentioning

confidence: 99%

Pseudo-complementary PNA actuators as reversible switches in dynamic DNA nanotechnology

Ackermann

Famulok

2013

Nucleic Acids Research

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“…It was long ago reported that condensation of the di-TMS congener of 2-thiothymine with the chloride 15 in benzene, and AgCU as catalyst, led to formation predominantly of the -anomer (ß/ = 1/2). 16 It is clear that, in our case, changing both the solvent and catalyst may significantly increase the yield of the ß-anomer. Similar results were obtained in the condensation reaction with the di-TMS derivative of 2-thiouracil (14), the overall yield for which was 60%, with ß/ (17/19) = 4/1.…”

Section: Chemistrymentioning

confidence: 64%

“…30 Xm» (pH 2) 273.5 nm (e 14 000), Xm., (pH 7.4) 270 nm (e 12 400). l-(2-Deoxy-3,5-di-0-j>-toluyl-/3-D-ribofuranosyl)-5-fluoro-2-thiouracil (16) and Its -Anomer (18). To a suspension of 365 mg (2.5 mmol) of 5-fluoro-2-thiouracil (11) in 25 mL of 1,4dioxane was added 10 mL of HMDS and 1 mL of TCS, and the mixture was heated under reflux for 20 h. The mixture was brought to dryness to give an oily residue, to which was added a solution of 970 mg (2.5 mmol) of l-chloro-2-deoxy-3,5-di-0p-toluyl-a-D-ribofuranose (15) in 30 mL of dichloroethane.…”

Section: Methodsmentioning

confidence: 99%

“…The same procedure converted 2-thiocytosine (10) to 2-thiouracil (12) in 50% yield. Initial trials at condensation of the di-TMS derivative of 5-fluoro-2-thiouracil (13) with 2-deoxy-3,5-di-0-p-toluyl-a-D-ribofuranosyl chloride (15) in 1,2-dichloroethane in the presence of TMS triflate, a weak Lewis acid, resulted in only a low yield (=10%) of a mixture of the blocked nucleoside anomers 16 and 18. Replacement of the triflate with stronger Lewis acids gave, with SnCL, about 30% of desired products, and with T1CI4 about 70% yield.…”

Section: Chemistrymentioning

confidence: 99%

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2-Thio derivatives of dUrd and 5-fluoro-dUrd and their 5'-monophosphates: synthesis, interaction with tumor thymidylate synthase, and in vitro antitumor activity

Bretner

Kulikowski²,

Dzik³

et al. 1993

J. Med. Chem.

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A convenient synthesis of 5-fluoro-2-thiouracil (11) is based on hydrolytic deamination of 5-fluoro-2-thiocytosine (9). Lewis acid-catalyzed condensation of di-TMS-5-fluoro-2-thiouracil (13) or di-TMS-2-thiouracil (14) with 2-deoxy-3,5-di-O-p-toluyl-D-ribofuranosyl chloride (15) led to mixtures of the beta- and alpha-anomers of 3',5'-toluylated 2'-deoxy-5-fluoro-2-thiouridine (16 and 18) or 2'-deoxy-2-thiouridine (17 and 19), each of which was deblocked with MeOH-NH3 to give the desired free anomeric nucleoside pairs 1, 5 and 3, 7, respectively. These were selectively converted to the corresponding 5'-monophosphates 2, 6 and 4, 8, with the aid of the wheat shoot phosphotransferase system. Conformations of the nucleosides 1, 3, 5, 7 are deduced from 1H NMR spectra, and circular dichroism spectra for nucleotide anomeric pairs 2, 6 and 4, 8 are reported. Whereas beta-2-thio-dUMP (4) was a good substrate (Km approximately 10(-5) M), beta-5-fluoro-2-thio-dUMP (2) proved to be a potent competitive, slow-binding inhibitor (Ki approximately 10(-8) M) of the purified enzymes from Ehrlich ascites carcinoma and L1210 cells. The alpha-anomer 6 was a weak inhibitor, with Ki in the mM range, and its congener 8 hardly interacted with the enzyme. The beta-anomer 1 exhibited antitumor activity in a mouse leukemic cell line L5178Y (IC50 approximately 10(-6) M), hence 40-100-fold weaker than 5-fluoro-dUrd. Its alpha-anomer 5 was 10-fold less active, but exhibited at least 10-fold higher selectivity with respect to the tumor cells than the beta-anomer 1.

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“…The organic phase was dried (MgS04) and evaporated leaving a foam (17.4 g) that was crystallized twice from ethanol giving 12.24 g (75%) of 6b with mp 156.5-157.5°( reported13 mp 157-158°). Chromatography of the mother liquors on a column of silicic acid using chloroform-ether (10:1), followed by crystallization from ethanol, gave a further 1.66 g (total yield 85%) of pure 6b: ^ 229 (e 42,000), 265 nm (12,800);Anal. Caled for C34H32N209 (616.64): C, 66.66; H, 5.27; N, 4.57.…”

Section: -Butyluracil (2)mentioning

confidence: 99%