A General and Enantioselective Approach to Pentoses: A Rapid Synthesis of PSI-6130, the Nucleoside Core of Sofosbuvir

Peifer, Manuel; Berger, Raphaëlle; Shurtleff, Valerie W.; Conrad, Jay C.; MacMillan, David W. C.

doi:10.1021/ja502205q

Cited by 76 publications

(61 citation statements)

References 25 publications

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“…Within this approach, nucleophilic substitution of ribonolactone ( Fig. 6 ) has garnered much attention [ 61 – 63 69 – 75 78 ]. Ribonolactone typically with its hydroxy groups protected, is amenable to nucleophilic substitutions [ 78 – 79 ].…”

Section: Reviewmentioning

confidence: 99%

“…In view of sugar scaffolds possessing C2' substitutions and their value to drug design, a report by Peifer et al on the synthesis of C2'-substituted ribonolactones is notable ( Fig. 11 ) [ 75 ]. Their finding appends known methods of C2' substitution that involve conversion of the C2'-OH to a ketone followed by Me or F substitution [ 87 – 94 ].…”

Section: Reviewmentioning

confidence: 99%

“…Their finding appends known methods of C2' substitution that involve conversion of the C2'-OH to a ketone followed by Me or F substitution [ 87 – 94 ]. Using the Mukaiyama aldol reaction, Peifer obtained a C2'-substituted ribonolactone, which can then be employed in C-nucleoside synthesis [ 75 ]. This involves condensation of alkyl-substituted silyl ketene acetals ( 32 ) with enantioenriched α-2,2,6,6-tetramethylpiperidinyl-β-benzyloxypropionaldehyde ( 33 ) in presence of TiCl 2 (OiPr) 2 to give the β-hydroxyester 34 that is diastereomerically enriched [ 75 , 95 ].…”

Section: Reviewmentioning

confidence: 99%

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Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

Temburnikar¹,

Seley‐Radtke²

2018

Beilstein J. Org. Chem.

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C-nucleosides have intrigued biologists and medicinal chemists since their discovery in 1950's. In that regard, C-nucleosides and their synthetic analogues have resulted in promising leads in drug design. Concurrently, advances in chemical syntheses have contributed to structural diversity and drug discovery efforts. Convergent and modular approaches to synthesis have garnered much attention in this regard. Among them nucleophilic substitution at C1' has seen wide applications providing flexibility in synthesis, good yields, the ability to maneuver stereochemistry as well as to incorporate structural modifications. In this review, we describe recent reports on the modular synthesis of C-nucleosides with a focus on D-ribonolactone and sugar modifications that have resulted in potent lead molecules.

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Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

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Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

Temburnikar¹,

Seley‐Radtke²

2018

Beilstein J. Org. Chem.

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“…In 2014, a team of Merck researchers published the synthesis of 2-deoxy-2,2-difluoro-Dribose according to their "de novo" approach (Scheme 101). 204 Optically active aldehyde 187 (83% ee) prepared through an enantioselective method, developed by the authors, was coupled with isopropyl bromodifluoroacetate under Reformatsky conditions: the suitably functionalized 895 pentanoate was obtained as a mixture of diastereoisomers 188. Purification by flash chromatography provided the required diastereoisomer in 59% yield.…”

Section: Synthesis Of Antitumor Fluorinated Pyrimidine Nucleosidesmentioning

confidence: 99%

Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

Ferraboschi

Ciceri

Grisenti

2017

Organic Preparations and Procedures International

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5-Fluorouracil35 Interest in the fluoropyrimidines stemmed from studies of the metabolism of uracil in rat hepatoma cells. The observation that these cells utilize uracil more avidly than normal rat intestinal mucosa prompted the preparation of fluorinated pyrimidines in order to improve disruption of tumor DNA biosynthesis. 3 In 1957 5-fluorouracil (5-FU) 1 was synthesized by Heidelberger et al., 4 with the aim of 40 blocking metabolism in malignant cells. The replacement of a hydrogen atom at C-5 by the fluorine atom modifies the interaction with the active sites of enzymes involved in metabolism. This antimetabolite, although toxic, is still one of the most widely used agents against solid tumors. Its action is due to two different mechanisms: 5 after penetration into the cell, 5-FU 1 is transformed into the 5-fluorouridine triphosphate that mimics UTP, is recognized by RNA 45 polymerase and consequently incorporated into RNA. The most significant action, however, is due to the 5-FU conversion into 5-fluoro-2 0 -deoxyuridine (FdUMP) 2, a known inhibitor of thymidylate synthetase (TS), a key enzyme in the DNA synthesis. 6,7 TS, in the presence of methylene tetrahydrofolate and deoxyuridine monophosphate (dUMP) 3 forms a ternary complex that catalyzes the substitution of 5-H uracil with a methyl group, affording thymine. If FdUMP 50 2 is present, the above ternary complex is not able to carry out this reaction, due to the presence of fluorine in the 5-position: the formation of TMP 4 (2 0 -deoxythymidine 5 0 -monophosphate), the only nucleotide precursor specific to DNA, is, therefore, blocked (Scheme 1), decreasing the availability of TTP (2 0 -deoxythymidine 5 0 -triphosphate) for DNA synthesis.Scheme 1 2 Ferraboschi, Ciceri, and GrisentiLater two additional mechanisms were proposed for 5-FU 1 antitumor activity: the 55 incorporation of 5-FU into DNA and the alteration of the membrane function of 5-FU 1 treated cells. Recent studies indicate that the TS-direct mechanism predominates when 1 is administered at low doses for a prolonged time, whereas the RNA-mediated process is more active following a bolus administration. 8-10 Synthesis of 5-FU 1, by construction of the pyrimidine ring, was first realized by Hei-60 delberger et al. in 1957 4,11,12 by reaction of a thiourea derivative 5 with the enolate of ethyl a-fluoro, a-formyl acetate 6 which, in turn, was obtained from methyl formate and ethyl fluoroacetate (Scheme 2). Depending on the chosen a-fluoro-b-ketoester the method is also applicable to the synthesis of other 5-fluoropyrimidines.An alternative method for the total synthesis is the direct fluorination of the pyrimi-65 dine ring of compound 7 by means of trifluoromethyl hypofluorite (CF 3 OF) 13 proposed by Robins in 1971. In the case of CF 3 OF in methanol/fluorotrichloromethane an intermediate was formed that, after treatment with triethylamine, afforded 5-FU 1 in 84% yield. 13 If the reaction was carried out with CF 3 OF in trifluoroacetic acid 1 was directly isolated in 85% yield. 14 The meth...

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“…This strategy bypasses the need for anomeric activation at the oxygen atom by synthesis of enantioselective prefabricated building blocks in which an appropriate leaving group, necessary during the coupling reaction with the nucleobase, is selectively introduced in the de novo synthetic sequence [ 36 , 37 , 38 , 39 ]. Other approaches also focused on modifying either the substituted nucleoside or the nucleobase [ 40 , 41 , 42 ].…”

Section: Gemcitabinementioning

confidence: 99%

Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery

et al. 2017

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Mesenchymal stromal cells are a population of undifferentiated multipotent adult cells possessing extensive self-renewal properties and the potential to differentiate into a variety of mesenchymal lineage cells. They express broad anti-inflammatory and immunomodulatory activity on the immune system and after transplantation can interact with the surrounding microenvironment, promoting tissue healing and regeneration. For this reason, mesenchymal stromal cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Another clinical application of mesenchymal stromal cells is the targeted delivery of chemotherapeutic agents to neoplastic cells, maximizing the cytotoxic activity against cancer cells and minimizing collateral damage to non-neoplastic tissues. Mesenchymal stem cells are home to the stroma of several primary and metastatic neoplasms and hence can be used as vectors for targeted delivery of antineoplastic drugs to the tumour microenvironment, thereby reducing systemic toxicity and maximizing antitumour effects. Paclitaxel and gemcitabine are the chemotherapeutic drugs best loaded by mesenchymal stromal cells and delivered to neoplastic cells, whereas other agents, like pemetrexed, are not internalized by mesenchymal stromal cells and therefore are not suitable for advanced antineoplastic therapy. This review focuses on the state of the art of advanced antineoplastic cell therapy and its future perspectives, emphasizing in vitro and in vivo preclinical results and future clinical applications.

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A General and Enantioselective Approach to Pentoses: A Rapid Synthesis of PSI-6130, the Nucleoside Core of Sofosbuvir

Cited by 76 publications

References 25 publications

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery

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