Synthesis of the First Selenium‐Containing Acyclic Nucleosides and Anomeric Spironucleosides from Carbohydrate Precursors

Maza, Susana; López, Óscar; Martos, Sergio; Maya, Inés; Fernandez‐Bolanos, J.

doi:10.1002/ejoc.200900793

Cited by 12 publications

(8 citation statements)

References 70 publications

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“…Other antitumor drugs in clinical use that target both DNA and TrxR include cisplatin, carmustine, ifosfamide, and doxorubicin . The Trx system is emerging as a novel target in cancer therapy, and several drugs that target Trx or TrxR are currently under development. − The finding that MMC inhibits TrxR lends further strength to the validation of TrxR as a target for anticancer drugs.…”

Section: Discussionmentioning

confidence: 99%

A New Mechanism of Action for the Anticancer Drug Mitomycin C: Mechanism-Based Inhibition of Thioredoxin Reductase

Paz

Zhang

et al. 2012

Chem. Res. Toxicol.

100

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Mitomycin C (MMC) is a chemotherapeutic drug that requires an enzymatic bioreduction to exert its biological effects. Upon reduction, MMC is converted into a highly reactive bis-electrophilic intermediate that alkylates cellular nucleophiles. Alkylation of DNA is the most favored mechanism of action for MMC, but other modes of action, such as redox cycling and inhibition of rRNA, may also contribute to the biological action of the drug. In this work, we show that thioredoxin reductase (TrxR) is also a cellular target for MMC. We show that MMC inhibits TrxR in vitro, using purified enzyme, and in vivo, using cancer cell cultures. The inactivation presents distinctive parameters of mechanism-based inhibitors: it is time- and concentration-dependent and irreversible. Additionally, spectroscopic experiments (UV, circular dichroism) show that the inactivated enzyme contains a mitosene chromophore. On the basis of kinetic and spectroscopic data, we propose a chemical mechanism for the inactivation of the enzyme that starts with a reduction of the quinone ring of MMC by the selenolthiol active site of TrxR and a subsequent alkylation of the active site by the activated drug. We also report that MMC inactivates TrxR in cancer cell cultures and that this inhibition correlates directly with the cytotoxicity of the drug, indicating that inhibition of TrxR may play a major role in the biological mode of action of the drug.

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Section: Discussionmentioning

confidence: 99%

A New Mechanism of Action for the Anticancer Drug Mitomycin C: Mechanism-Based Inhibition of Thioredoxin Reductase

Paz

Zhang

et al. 2012

Chem. Res. Toxicol.

100

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“…Nevertheless, for R = alkyl or aryl groups lacking the sulfonamido moiety, a spontaneous intramolecular cyclization was previously observed [29] to give a Access to targeted bicyclic imidazolidine-2-thiones was carried out by using the methodology developed by some of us for preparing pseudo-nucleosides [29][30][31] and their selenium isosters [32]. Such a synthetic pathway involves the preparation of a transient thiourea on the C-2 of a reducing carbohydrate (Scheme 1), derived from 2-deoxy-2-amino-D-sugars.…”

Section: Drug Design and Chemistrymentioning

confidence: 99%

Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors

Martínez-Montiel

Romero-Hernández

Giovannuzzi

et al. 2023

IJMS

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The involvement of carbonic anhydrases (CAs) in a myriad of biological events makes the development of new inhibitors of these metalloenzymes a hot topic in current Medicinal Chemistry. In particular, CA IX and XII are membrane-bound enzymes, responsible for tumour survival and chemoresistance. Herein, a bicyclic carbohydrate-based hydrophilic tail (imidazolidine-2-thione) has been appended to a CA-targeting pharmacophore (arylsulfonamide, coumarin) with the aim of studying the influence of the conformational restriction of the tail on the CA inhibition. For this purpose, the coupling of sulfonamido- or coumarin-based isothiocyanates with reducing 2-aminosugars, followed by the sequential acid-promoted intramolecular cyclization of the corresponding thiourea and dehydration reactions, afforded the corresponding bicyclic imidazoline-2-thiones in good overall yield. The effects of the carbohydrate configuration, the position of the sulfonamido motif on the aryl fragment, and the tether length and substitution pattern on the coumarin were analysed in the in vitro inhibition of human CAs. Regarding sulfonamido-based inhibitors, the best template turned out to be a d-galacto-configured carbohydrate residue, meta-substitution on the aryl moiety (9b), with Ki against CA XII within the low nM range (5.1 nM), and remarkable selectivity indexes (1531 for CA I and 181.9 for CA II); this provided an enhanced profile in terms of potency and selectivity compared to more flexible linear thioureas 1‒4 and the drug acetazolamide (AAZ), used herein as a reference compound. For coumarins, the strongest activities were found for substituents devoid of steric hindrance (Me, Cl), and short linkages; derivatives 24h and 24a were found to be the most potent inhibitors against CA IX and XII, respectively (Ki = 6.8, 10.1 nM), and also endowed with outstanding selectivity (Ki > 100 µM against CA I, II, as off-target enzymes). Docking simulations were conducted on 9b and 24h to gain more insight into the key inhibitor–enzyme interactions.

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“…Fernández-Bolaños and co-workers synthesized the first selenium-containing C -1′-spironucleosides. 55 The precursors 103 and 104 were obtained from the reaction of N -arylfructosamines 100 and 101 with phenyl and p -tolyl isoselenocyanates 102 , respectively (Scheme 15 ). Then 103 and 104 underwent dehydration under weakly acidic conditions to form the stable carbocations and the major product, spiro compounds 107 and 108 were obtained due to nucleophilic attack of the hydroxyl group present on C -3′ of the alkyl chain (Scheme 16 ).…”

Section: -1′-spirocyclic Nucleosidesmentioning

confidence: 99%

Advances in the Synthesis of Spirocyclic Nucleosides

Kumar,

Khan,

Arora

et al. 2023

Synthesis

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The nucleosides are the building blocks for nucleic acids and composed of a five-carbon sugar bearing either pyrimidine or purine nucleobase. The biological properties of nucleosides can be tailored by chemically modifying the five-carbon sugar to influence its sugar pucker. The spirocyclic scaffold is an indispensable scaffold in more than ten approved drugs, and its inherent three-dimensionality makes it an ideal modification to influence the sugar pucker and biological properties of nucleosides. However, the introduction of spirocyclic scaffold is often synthetically challenging due to increase in synthetic steps and stereocenters. The present review highlights the advances in synthetic methodologies developed during the past decades for accessing various members of the spiro-functionalized nucleoside family.1 Introduction2 C-1′-Spirocyclic Nucleosides3 C-2′-Spirocyclic Nucleosides4 C-3′-Spirocyclic Nucleosides5 C-4′-Spirocyclic Nucleosides6 Miscellaneous Spirocyclic Nucleosides7 Conclusion and Future Perspectives

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Synthesis of the First Selenium‐Containing Acyclic Nucleosides and Anomeric Spironucleosides from Carbohydrate Precursors

Cited by 12 publications

References 70 publications

A New Mechanism of Action for the Anticancer Drug Mitomycin C: Mechanism-Based Inhibition of Thioredoxin Reductase

A New Mechanism of Action for the Anticancer Drug Mitomycin C: Mechanism-Based Inhibition of Thioredoxin Reductase

Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors

Advances in the Synthesis of Spirocyclic Nucleosides

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