Studies in Chemotherapy. X. Antithyroid Compounds. Synthesis of 5- and 6- Substituted 2-Thiouracils from β-Oxoesters and Thiourea<sup>1</sup>

Anderson, Gaylord W.; Halverstadt, I. F.; Miller, Wilbur H.; Roblin, Richard O.

doi:10.1021/ja01228a042

Cited by 121 publications

(25 citation statements)

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“…In contrast to the thionated DNA derivatives, thionated RNA derivatives are among the most highly conserved and ubiquitous nucleobases in bacterial tRNAs (11). Since their discovery in the mid-1900s, thiopyrimidine derivatives have been employed in structural-biology studies (207)(208)(209)(210) and investigated for their potential pharmacological properties (5,(211)(212)(213)(214). 4-Thiouracil is widely used in photocrosslinking investigations to uncover in vivo RNA structures and important RNA-protein interactions (15,19,43,201,202,204,215).…”

Section: Thiobases As Phototherapeutic and Photocrosslinking Agentsmentioning

confidence: 99%

Photochemical and Photodynamical Properties of Sulfur‐Substituted Nucleic Acid Bases,

Ashwood

Pollum

Crespo‐Hernández

2018

Photochem & Photobiology

107

132

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Sulfur-substituted nucleobases (a.k.a., thiobases) are among the world's leading prescriptions for chemotherapy and immunosuppression. Long-term treatment with azathioprine, 6-mercaptopurine and 6-thioguanine has been correlated with the photoinduced formation of carcinomas. Establishing an in-depth understanding of the photochemical properties of these prodrugs may provide a route to overcoming these carcinogenic side effects, or, alternatively, a basis for developing effective compounds for targeted phototherapy. In this review, a broad examination is undertaken, surveying the basic photochemical properties and excited-state dynamics of sulfur-substituted analogs of the canonical DNA and RNA nucleobases. A molecular-level understanding of how sulfur substitution so remarkably perturbs the photochemical properties of the nucleobases is presented by combining experimental results with quantum-chemical calculations. Structure-property relationships demonstrate the impact of site-specific sulfur substitution on the photochemical properties, particularly on the population of the reactive triplet state. The value of fundamental photochemical investigations for driving the development of ultraviolet-A chemotherapeutics is showcased. The most promising photodynamic agents identified thus far have been investigated in various carcinoma cell lines and shown to decrease cell proliferation upon exposure to ultraviolet-A radiation. Overarching principles have been elucidated for the impact that sulfur substitution of the carbonyl oxygen has on the photochemical properties of the nucleobases.

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Section: Thiobases As Phototherapeutic and Photocrosslinking Agentsmentioning

confidence: 99%

Photochemical and Photodynamical Properties of Sulfur‐Substituted Nucleic Acid Bases,

Ashwood

Pollum

Crespo‐Hernández

2018

Photochem & Photobiology

107

132

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“…One of the most actively investigated class of nucleobase analogues are the thio-nucleobases (thiobases), where an oxygen atom of a canonical base is replaced by sulfur. These compounds have some pharmaceutic [ 12 , 13 , 14 , 15 ] and photo-chemotherapeutic [ 16 , 17 , 18 ] applications because they exhibit a very interesting photophysics involving ultrafast intersystem crossing (ISC) with near-unity quantum yields [ 8 , 9 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Simulated and Experimental Time-Resolved Photoelectron Spectra of the Intersystem Crossing Dynamics in 2-Thiouracil

et al. 2018

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We report time-dependent photoelectron spectra recorded with a single-photon ionization setup and extensive simulations of the same spectra for the excited-state dynamics of 2-thiouracil (2TU) in the gas phase. We find that single-photon ionization produces very similar results as two-photon ionization, showing that the probe process does not have a strong influence on the measured dynamics. The good agreement between the single-photon ionization experiments and the simulations shows that the norms of Dyson orbitals allow for qualitatively describing the ionization probabilities of 2TU. This reasonable performance of Dyson norms is attributed to the particular electronic structure of 2TU, where all important neutral and ionic states involve similar orbital transitions and thus the shape of the Dyson orbitals do not strongly depend on the initial neutral and final ionic state. We argue that similar situations should also occur in other biologically relevant thio-nucleobases, and that the time-resolved photoelectron spectra of these bases could therefore be adequately modeled with the techniques employed here.

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“…Initially, the synthesis of intermediate 5 was achieved through keto ester 7 ( Scheme 2 ). The synthesis of compound 7 was reported many years ago [ 27 , 28 ]. Unfortunately, in our case, the classic C–C coupling involving Claisen or Grignard, as well as Reformatsky and aldol, reactions led to unexpected byproducts.…”

Section: Resultsmentioning

confidence: 99%

An Efficient Chemoenzymatic Approach towards the Synthesis of Rugulactone

2018

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Rugulactone is a natural product isolated from the plant Cryptocarya rugulosa. It has shown very important biological activity as an inhibitor of the nuclear factor κB (NF-κB) activation pathway. A new chemoenzymatic approach towards the synthesis of rugulactone is presented here. The chirality, induced to the key intermediate by a stereoselective enzymatic reduction utilizing NADPH-dependent ketoreductase, is described in detail.

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Studies in Chemotherapy. X. Antithyroid Compounds. Synthesis of 5- and 6- Substituted 2-Thiouracils from β-Oxoesters and Thiourea¹

Cited by 121 publications

References 0 publications

Photochemical and Photodynamical Properties of Sulfur‐Substituted Nucleic Acid Bases,

Photochemical and Photodynamical Properties of Sulfur‐Substituted Nucleic Acid Bases,

Simulated and Experimental Time-Resolved Photoelectron Spectra of the Intersystem Crossing Dynamics in 2-Thiouracil

An Efficient Chemoenzymatic Approach towards the Synthesis of Rugulactone

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Studies in Chemotherapy. X. Antithyroid Compounds. Synthesis of 5- and 6- Substituted 2-Thiouracils from β-Oxoesters and Thiourea1

Cited by 121 publications

References 0 publications

Photochemical and Photodynamical Properties of Sulfur‐Substituted Nucleic Acid Bases,

Photochemical and Photodynamical Properties of Sulfur‐Substituted Nucleic Acid Bases,

Simulated and Experimental Time-Resolved Photoelectron Spectra of the Intersystem Crossing Dynamics in 2-Thiouracil

An Efficient Chemoenzymatic Approach towards the Synthesis of Rugulactone

Contact Info

Product

Resources

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Studies in Chemotherapy. X. Antithyroid Compounds. Synthesis of 5- and 6- Substituted 2-Thiouracils from β-Oxoesters and Thiourea¹