Expanding a fluorescent RNA alphabet: synthesis, photophysics and utility of isothiazole-derived purine nucleoside surrogates

Rovira, Alexander R.; Fin, Andréa; Tor, Yitzhak

doi:10.1039/c6sc05354h

Cited by 57 publications

(43 citation statements)

References 67 publications

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“…Further exploiting this synthetic route, Tor and co‐workers reported an expansion of their previous work on the synthesis of 4‐aminoisothiazoles by a Thorpe–Ziegler‐type cyclization (Scheme ) . This method rapidly delivers C‐5 unsubstitued 4‐aminoisothiazoles containing amino and carbonyl functional handles for further derivatization.…”

Section: Synthesis Of Isothiazolesmentioning

confidence: 99%

Recent Advances in the Synthesis and Reactivity of Isothiazoles

2019

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Isothiazoles represent an important class of five‐membered sulfur heterocycles that are widely utilized in medicinal chemistry and organic synthesis due to the unique properties of two electronegative heteroatoms in a 1,2‐relationship. However, in contrast to other 1,2‐azoles, the facile assembly of isothiazoles has always been considered a substantial challenge. In the last decade, major advances have taken place in the fields of synthesis and functionalization of isothiazoles that make them accessible to a wide range of interested chemists through unprecedented pathways. New condensation methods have emerged that address the challenges posed by unstable thiohydroxylamine. New metal‐catalyzed approaches have been reported that deliver densely decorated isothiazoles bearing various sensitive functional groups. New functionalization strategies have been developed through both cross‐coupling and direct C−H activation chemistry. Finally, the emergence of novel heterocyclic architectures based on isothiazole opens the door for future investigations of this versatile heterocyclic scaffold. This review covers the period from January 2004 to December 2018 and is intended as a sequel to the review on isoxazoles, which represent another class of synthetically‐important 1,2‐azoles (see Adv. Synth. Catal. 2015, 357, 2583–2614).

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Section: Synthesis Of Isothiazolesmentioning

confidence: 99%

Recent Advances in the Synthesis and Reactivity of Isothiazoles

2019

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“…All values reflect the average of at least three independent measurements. See Table S1 for experimental errors. b See references 17 and 19. c Measured in Milli-Q water. d Measured in Tris buffer pH 7.6. e Measured at ADH reaction end, assuming complete consumption, Tris buffer pH 7.6. …”

Section: Figurementioning

confidence: 99%

“…To prepare N tz AD + , the previously synthesized tz A 19 was treated with POCl 3 and trimethyl phosphate to give tz AMP (Scheme 1), which was coupled to activated β -nicotinamide mononucleotide following published protocols. 11c,21 The spectroscopic properties of N tz AD + closely resemble that of tz A , the core nucleoside.…”

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Emissive Synthetic Cofactors: An Isomorphic, Isofunctional, and Responsive NAD⁺ Analogue

2017

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The synthesis, photophysics, and biochemical utility of a fluorescent NAD+ analogue based on an isothiazolo[4,3-d]pyrimidine core (NtzAD+) are described. Enzymatic reactions, photophysically monitored in real time, show NtzAD+ and NtzADH to be substrates for yeast alcohol dehydrogenase and lactate dehydrogenase, respectively, with reaction rates comparable to that of the native cofactors. A drop in fluorescence is seen as NtzAD+ is converted to NtzADH, reflecting a complementary photo-physical behavior to that of the native NAD+/NADH. NtzAD+ and NtzADH serve as substrates for NADase, which selectively cleaves the nicotinamide’s glycosidic bond yielding tzADP-ribose. NtzAD+ also serves as a substrate for ribosyl transferases, including human adenosine ribosyl transferase 5 (ART5) and Cholera toxin subunit A (CTA), which hydrolyze the nicotinamide and transfer tzADP-ribose to an arginine analogue, respectively. These reactions can be monitored by fluorescence spectroscopy, in stark contrast to the corresponding processes with the nonemissive NAD+.

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“…[3,6] A guiding principle for the successful advancement of such probes is to curtail structural and functional perturbations (features defined as isomorphicity and isofunctionality, respectively), while endowing them with useful photophysical attributes. Several families of emissive analogues have been made and employed, [6] with emissive RNA alphabets based on the thiopheno[3,4- d ]pyrimidine ( th N ) [7] and the isothiazolo[4,3- d ]pyrimidine-cores ( tz N ) [8] being most notable. [9–11] …”

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Emissive Synthetic Cofactors: Enzymatic Interconversions of ^tzA Analogues of ATP, NAD⁺, NADH, NADP⁺, and NADPH

et al. 2017

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A series of enzymatic transformations, which generate visibly emissive isofunctional cofactors based on an isothiazolo[4,3-d]pyrimidine analogue of adenosine ( A), was developed. Nicotinamide adenylyl transferase condenses nicotinamide mononucleotide and ATP to yield N AD , which can be enzymatically phosphorylated by NAD kinase and ATP or ATP to the corresponding N ADP . The latter can be engaged in NADP-specific coupled enzymatic transformations involving conversion to N ADPH by glucose-6-phosphate dehydrogenase and reoxidation to N ADP by glutathione reductase. The N ADP /N ADPH cycle can be monitored in real time by fluorescence spectroscopy.

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Expanding a fluorescent RNA alphabet: synthesis, photophysics and utility of isothiazole-derived purine nucleoside surrogates

Abstract: A series of emissive ribonucleoside purine mimics, all comprised of an isothiazolo[4,3-d]pyrimidine core, was prepared using a divergent pathway involving a key Thorpe–Ziegler cyclization.

Cited by 57 publications

References 67 publications

Recent Advances in the Synthesis and Reactivity of Isothiazoles

Recent Advances in the Synthesis and Reactivity of Isothiazoles

Emissive Synthetic Cofactors: An Isomorphic, Isofunctional, and Responsive NAD⁺ Analogue

Emissive Synthetic Cofactors: Enzymatic Interconversions of ^tzA Analogues of ATP, NAD⁺, NADH, NADP⁺, and NADPH

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Expanding a fluorescent RNA alphabet: synthesis, photophysics and utility of isothiazole-derived purine nucleoside surrogates

Abstract: A series of emissive ribonucleoside purine mimics, all comprised of an isothiazolo[4,3-d]pyrimidine core, was prepared using a divergent pathway involving a key Thorpe–Ziegler cyclization.

Cited by 57 publications

References 67 publications

Recent Advances in the Synthesis and Reactivity of Isothiazoles

Recent Advances in the Synthesis and Reactivity of Isothiazoles

Emissive Synthetic Cofactors: An Isomorphic, Isofunctional, and Responsive NAD+ Analogue

Emissive Synthetic Cofactors: Enzymatic Interconversions of tzA Analogues of ATP, NAD+, NADH, NADP+, and NADPH

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Emissive Synthetic Cofactors: An Isomorphic, Isofunctional, and Responsive NAD⁺ Analogue

Emissive Synthetic Cofactors: Enzymatic Interconversions of ^tzA Analogues of ATP, NAD⁺, NADH, NADP⁺, and NADPH