Discovery of benzophosphadiazine drug candidate IDX375: A novel hepatitis C allosteric NS5B RdRp inhibitor

Paparin, Jean-Laurent; Amador, Agnès; Badaroux, Eric; Bot, Stéphanie; Caillet, Catherine; Convard, Thierry; Costa, Daniel Da; Dukhan, David; Griffe, Ludovic; Griffon, Jean-François; LaColla, M.; Leroy, Frédéric; Liuzzi, Michel; Loi, A. G.; McCarville, Joe; Mascia, Valeria; Milhau, Julien; Onidi, Loredana; Pierra, Claire; Rahali, Rachid; Rosinosky, Elodie; Sais, Efisio; Seifer, Maria; Surleraux, Dominique; Standring, David N.; Dousson, Cyril B.

doi:10.1016/j.bmcl.2017.01.017

Cited by 10 publications

(4 citation statements)

References 21 publications

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“…In addition, treatment of 2-Cl-2-F lactol 31 (7/1) under the same conditions allowed us to isolate in excellent yields the corresponding uracil and cytosine derivatives 33 and 44 as 3/1 and 5/1 mixtures, respectively (Scheme ). Compounds 33 , 34 , 43 , and 44 were deprotected using the method we previously described , (either with Et 3 N·3HF or tetra - N -butylammonium fluoride) to afford the corresponding β nucleoside analogues (>95% purity).…”

Section: Resultsmentioning

confidence: 99%

Diastereoselective Synthesis of 2′-Dihalopyrimidine Ribonucleoside Inhibitors of Hepatitis C Virus Replication

Zhou

Zhang

et al. 2021

ACS Omega

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We present a newly developed synthetic route to 2-bromo-2-fluoro ribolactone based on our published 2-chloro-2-fluoro ribolactone synthesis. Stereoselective fluorination is key to controlling the 2-diastereoselectivity. We also report a substantially improved glycosylation reaction with both the 2-bromo-2-fluoro and 2-chloro-2-fluoro sugars. These improvements allowed us to prepare 2′-dihalo nucleosides 13 and 14 in an overall 15–20% yield.

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Section: Resultsmentioning

confidence: 99%

Diastereoselective Synthesis of 2′-Dihalopyrimidine Ribonucleoside Inhibitors of Hepatitis C Virus Replication

Zhou

Zhang

et al. 2021

ACS Omega

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“…The presence of fluorine at the 2 0 -position can provide acidic and enzymatic stabilities to the glycosidic bond 174 and the gem-difluoromethylene group is an isopolar and isosteric substituent for oxygen. 175 Extensive studies about the 2 0 -position 755 modification with atoms or groups other than hydrogen or hydroxy (for example Cl, 176 , N 3 , 177 Se, 178 CH 3 , 179,180 ) have been performed, since the presence of a hydroxy or a hydrogen distinguishes nucleosides as components of RNA or DNA.…”

Section: Pyrimidine Nucleosides Fluorinated At the Sugar Moietymentioning

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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“…[4,5] More recently, however, greater attention has also been paid to phosphonamidates, for example in antivirals such as the HIV drug tenofovir alafenamide (5) and in the DOPO (9,10-dihydro-9-oxa-10-phospha-phenanthrene-10-oxide) class of flame retardants (6). [2,[6][7][8] In the design of bioactive compounds for medicinal or other applications, this moiety attracts attention by serving as a bioisostere to both sulfonamide [9][10][11] and carboxamide moieties. [6,11,12] Whereas phosphonates are generally highly resistant to hydrolysis, [13] phosphonamidates are more easily hydrolyzed and thus often more suitable as prodrugs.…”

Section: Introductionmentioning

confidence: 99%

Triethylamine‐Mediated Transformation of Phosphonates into Phosphonamidates

Backx,

Dejaegere,

Simoens

et al. 2023

Eur J Org Chem

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Organophosphorus compounds such as phosphonamidates are gaining attention across different fields of chemistry, with interesting applications as pharmaceuticals, or pesticides. However, practical application of phosphonamidates is complicated by their difficult syntheses which often involve expensive or unstraightforward reagents and harsh conditions. To remedy these issues, we present a flexible, room temperature synthesis for novel P‐alkylphosphonamidates without the need for intermediary purification. Commonly available phosphonates are first chlorinated by use of oxalyl chloride and phosphonylaminium salts are used to mediate the harsh reactivity of phosphonochloridates, giving rise to the desired products. We demonstrate the compatibility of our protocol with primary and secondary amines, as well as with different phosphonate esters. The proposed pathway also enables the synthesis of primary phosphonamidates using ammonium acetate as a cheap and safe alternative for ammonia. In future research, this protocol will also enable the synthesis of bioactive targets that are incompatible with current protocols.

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Discovery of benzophosphadiazine drug candidate IDX375: A novel hepatitis C allosteric NS5B RdRp inhibitor

Cited by 10 publications

References 21 publications

Diastereoselective Synthesis of 2′-Dihalopyrimidine Ribonucleoside Inhibitors of Hepatitis C Virus Replication

Diastereoselective Synthesis of 2′-Dihalopyrimidine Ribonucleoside Inhibitors of Hepatitis C Virus Replication

Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

Triethylamine‐Mediated Transformation of Phosphonates into Phosphonamidates

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