Synthesis of 3-(2'-deoxy-D-erythro-pentofuranosyl)adenine.  Application of a new protecting group, pivaloyloxymethyl(Pom)

Rasmussen, M; Leonard, Nelson J.

doi:10.1021/ja00997a026

Cited by 68 publications

(36 citation statements)

References 10 publications

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“…8 For example, the pivaloyloxymethyl (POM) derivative 9 is much more hydrophobic in terms of a calculated ClogP and also demonstrates cellular activity at lower concentrations. 10 More recently, we have prepared some triazole bisphosphonates through click chemistry 11 of an acetylene bisphosphonate 12 and various isoprenoid azides.…”

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confidence: 99%

Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

Wills

Allen

Holstein

et al. 2015

ACS Med. Chem. Lett.

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Studies of triazole bisphosphonates have resulted in identification of a potent inhibitor of geranylgeranyl diphosphate synthase (IC 50 = 45 nM) with very good selectivity for this enzyme over farnesyl diphosphate synthase (IC 50 = 28 μM). This compound also potently disrupts geranylgeranylation and induces cytotoxicity in human myeloma cells at submicromolar levels, suggesting that it may serve as a lead compound for treatment of malignancies characterized by excessive protein secretion.

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mentioning

confidence: 99%

Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

Wills

Allen

Holstein

et al. 2015

ACS Med. Chem. Lett.

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“…We have applied the commonly-used [3] non-fluorescent pivaloyloxymethyl (POM) [13] protecting group to both phosphonates [14] and bisphosphonates [15] and observed strong gains in cellular potency, but lacked ways to easily quantify uptake in live cells. Here, we focused on a derivative of the HMBPP analogue ( E )-4-hydroxy-3-methyl-but-2-enyl phosphonate ( 2 , C-HMBP).…”

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confidence: 99%

Evaluation of a 7‐Methoxycoumarin‐3‐carboxylic Acid Ester Derivative as a Fluorescent, Cell‐Cleavable, Phosphonate Protecting Group

et al. 2015

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Cell-cleavable protecting groups often enhance cellular delivery of species that are charged at physiological pH. Although several phosphonate protecting groups have achieved clinical success, it remains difficult to use these prodrugs in live cells to clarify biological mechanisms. Here we present a strategy that uses a 7-methoxycoumarin-3-carboxylic acid ester as a fluorescent protecting group. This strategy is applied to synthesis of an HMBPP analogue to assess cellular uptake and human Vγ9Vδ2 T cell activation. The fluorescent ester displays low cell toxicity (IC50 >100 μM) and strong T cell activation (EC50 = 0.018 μM) relative to the unprotected anion (EC50 = 23 μM). The coumarin-derived analogue allows no-wash analysis of biological deprotection, which reveals rapid internalization of the prodrug. These results demonstrate that fluorescent groups can be applied both as functional drug delivery tools and useful biological probes of drug uptake.

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“…11 Various analyses of cell lysate easily can distinguish between compounds that inhibit GGDPS and those that inhibit geranylgeranyl transferase I and/or II (GGTase I and GGTase II), thus providing information on both activity and selectivity from one assay. The specific prodrug form selected was the pivaloyloxymethyl or POM group, in part because of its long history 12 and in part because it already is in clinical use in both antibiotics 13 and especially in antiviral agents. 14 The POM group is cleaved by nonspecific esterases within the cell, which liberates pivalic acid, formaldehyde, and the phosphonic acid, while simple alkyl esters of phosphonic acids are far more stable to metabolism.…”

Section: Synthesismentioning

confidence: 99%

A new motif for inhibitors of geranylgeranyl diphosphate synthase

Foust

Allen

Holstein

et al. 2016

Bioorganic & Medicinal Chemistry

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The enzyme geranylgeranyl diphosphate synthase (GGDPS) is believed to receive the substrate farnesyl diphosphate through one lipophilic channel and release the product geranylgeranyl diphosphate through another. Bisphosphonates with two isoprenoid chains positioned on the α-carbon have proven to be effective inhibitors of this enzyme. Now a new motif has been prepared with one isoprenoid chain on the α-carbon, a second included as a phosphonate ester, and the potential for a third at the α-carbon. The pivaloyloxymethyl prodrugs of several compounds based on this motif have been prepared and the resulting compounds have been tested for their ability to disrupt protein geranylgeranylation and induce cytotoxicity in myeloma cells. The initial biological studies reveal activity consistent with GGDPS inhibition, and demonstrate a structure-function relationship which is dependent on the nature of the alkyl group at the α-carbon.

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Synthesis of 3-(2'-deoxy-D-erythro-pentofuranosyl)adenine. Application of a new protecting group, pivaloyloxymethyl(Pom)

Cited by 68 publications

References 10 publications

Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

Evaluation of a 7‐Methoxycoumarin‐3‐carboxylic Acid Ester Derivative as a Fluorescent, Cell‐Cleavable, Phosphonate Protecting Group

A new motif for inhibitors of geranylgeranyl diphosphate synthase

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