Synthesis and Evaluation of Prodrugs of α-Carboxy Nucleoside Phosphonates
A range of lipophilic prodrugs of α-carboxy nucleoside phosphonates, potent inhibitors of HIV-1 reverse transcriptase without requiring prior phosphorylation, were synthesized to evaluate their in vivo potency against HIV in cell culture. A series of prodrug derivatives bearing a free carboxylic acid where the phosphonate was masked with bispivaloyloxymethyl, diisopropyloxycarbonyloxymethyl, bisamidate, aryloxyphosphoramidate, hexadecyloxypropyl, CycloSal, and acycloxybenzyl moieties were synthesized, adapting existing methodologies for phosphonate protection to accommodate the adjacent carboxylic acid moiety. The prodrugs were assayed for anti-HIV activity in CEM cell cultures─the bispivaloyloxymethyl free acid monophosphonate prodrug exhibited some activity (inhibitory concentration-50 (IC50) 59 ± 17 μM), while the other prodrugs were inactive at 100 μM. A racemic bispivaloyloxymethyl methyl ester monophosphonate prodrug was also prepared to assess the suitability of the methyl ester as a carboxylic acid prodrug. This compound exhibited no activity against HIV in cellular assays.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:87 |
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| Enthalten in: |
The Journal of organic chemistry - 87(2022), 21 vom: 04. Nov., Seite 14793-14808 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ford, Alan [VerfasserIn] |
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| Links: |
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| Themen: |
Anti-HIV Agents |
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| Anmerkungen: |
Date Completed 08.11.2022 Date Revised 06.01.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.joc.2c02135 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM347975712 |
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| 245 | 1 | 0 | |a Synthesis and Evaluation of Prodrugs of α-Carboxy Nucleoside Phosphonates |
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| 500 | |a Date Revised 06.01.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a A range of lipophilic prodrugs of α-carboxy nucleoside phosphonates, potent inhibitors of HIV-1 reverse transcriptase without requiring prior phosphorylation, were synthesized to evaluate their in vivo potency against HIV in cell culture. A series of prodrug derivatives bearing a free carboxylic acid where the phosphonate was masked with bispivaloyloxymethyl, diisopropyloxycarbonyloxymethyl, bisamidate, aryloxyphosphoramidate, hexadecyloxypropyl, CycloSal, and acycloxybenzyl moieties were synthesized, adapting existing methodologies for phosphonate protection to accommodate the adjacent carboxylic acid moiety. The prodrugs were assayed for anti-HIV activity in CEM cell cultures─the bispivaloyloxymethyl free acid monophosphonate prodrug exhibited some activity (inhibitory concentration-50 (IC50) 59 ± 17 μM), while the other prodrugs were inactive at 100 μM. A racemic bispivaloyloxymethyl methyl ester monophosphonate prodrug was also prepared to assess the suitability of the methyl ester as a carboxylic acid prodrug. This compound exhibited no activity against HIV in cellular assays | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Mullins, Nicholas D |e verfasserin |4 aut | |
| 700 | 1 | |a Balzarini, Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Maguire, Anita R |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of organic chemistry |d 1945 |g 87(2022), 21 vom: 04. Nov., Seite 14793-14808 |w (DE-627)NLM000006343 |x 1520-6904 |7 nnns |
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