Stereoselective Synthesis of Homoneryl and Homogeranyl Triazole Bisphosphonates

Matthiesen, Robert A.; Wills, Veronica S.; Metzger, Joseph I.; Holstein, Sarah A.; Wiemer, David F.

doi:10.1021/acs.joc.6b01693

Cited by 23 publications

(22 citation statements)

References 31 publications

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“…[ 14 C]-IPP was purchased from American Radiolabeled Chemicals (St. Louis, MO). The pure homogeranyl and homoneryl triazole bisphosphonates (7 and 8) and the 3:1 (HG:HN) mixture (6) were prepared as previously reported (Wills et al, 2015;Matthiesen et al, 2016). Stock solutions (50 mM) of the triazole bisphosphonate sodium salts were prepared in sterile water and stored at 220°C.…”

Section: Methodsmentioning

confidence: 99%

“…1) was identified as the most potent inhibitor of GGDPS described to date with an IC 50 of 45 nM (Wills et al, 2015). Given the relative activities of the geranyl/neryl isomers, one might predict that the homoneryl isomer would be significantly more potent than the homogeranyl isomer, and efforts have therefore been focused on the preparation of the pure isomers (Matthiesen et al, 2016). Here we present our findings for the biologic activities of the homogeranyl and homoneryl triazole bisphosphonates and demonstrate that these compounds interact in a synergistic manner to inhibit GGDPS, thus establishing a new paradigm for the development of GGDPS inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

et al. 2017

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The isoprenoid donor for protein geranylgeranylation reactions, geranylgeranyl diphosphate (GGDP), is the product of the enzyme GGDP synthase (GGDPS) that condenses farnesyl diphosphate (FDP) and isopentenyl pyrophosphate. GGDPS inhibition is of interest from a therapeutic perspective for multiple myeloma because we have shown that targeting Rab GTPase geranylgeranylation impairs monoclonal protein trafficking, leading to endoplasmic reticulum stress and apoptosis. We reported a series of triazole bisphosphonate GGDPS inhibitors, of which the most potent was a 3:1 mixture of homogeranyl (HG) and homoneryl (HN) isomers. Here we determined the activity of the individual olefin isomers. Enzymatic and cellular assays revealed that although HN is approximately threefold more potent than HG, HN is not more potent than the original mixture. Studies in which cells were treated with varying concentrations of each isomer alone and in different combinations revealed that the two isomers potentiate the induced-inhibition of protein geranylgeranylation when used in a 3:1 HG:HN combination. A synergistic interaction was observed between the two isomers in the GGDPS enzyme assay. These results suggested that the two isomers bind simultaneously to the enzyme but within different domains. Computational modeling studies revealed that HN is preferred at the FDP site, that HG is preferred at the GGDP site, and that both isomers may bind to the enzyme simultaneously. These studies are the first to report a set of olefin isomers that synergistically inhibit GGDPS, thus establishing a new paradigm for the future development of GGDPS inhibitors.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

et al. 2017

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“…In this case the ratio of olefin isomers was determined from the average integration of resonances corresponding to the sp 2 olefin carbons (137.7 and 133.7 ppm for the Z -isomer and 137.6 and 133.5 ppm for the E -isomer) and the adjacent methylene group (31.1 ppm for the Z -isomer and 38.9 ppm for the E -isomer) in the 13 C NMR spectrum. 11 The 13 C NMR spectrum of the geranyl-derived triazole 17b indicated that this analogue was a single isomer within the limits of detection.…”

Section: Synthesismentioning

confidence: 99%

“…The ratio was determined by integration of the resonances at 32.1 and 39.9 ppm, which correspond to the methylene carbon at C-6. 11,22 Because the E -isomer was such a minor component, the mixture was carried forward. The primary alcohols then were allowed to react with MsCl and Et 3 N followed by LiBr to afford the corresponding bishomoallylic bromides 13a , 23 13b , 24 and 13c in low to moderate yields.…”

Section: Synthesismentioning

confidence: 99%

“…10 Synthesis of the pure isomers allowed assessment of the biological activities of the individual compounds. 11 These studies revealed that while the homoneryl isomer ( 6 ) was more potent than the homogeranyl isomer ( 4 ), when used in combination the two isomers exhibited synergistic inhibitory effects on the target enzyme. 12 Modeling studies suggested that the homoneryl isomer ( 6 ) preferentially binds to the FDP site while the homogeranyl isomer ( 4 ) preferentially binds to the GGDP site, thus establishing a new paradigm for the development of GGDPS inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase

Wills

Metzger

Allen

et al. 2017

Bioorganic & Medicinal Chemistry

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Protein geranylgeranylation reactions are dependent on the availability of geranylgeranyl diphosphate (GGDP), which serves as the isoprenoid donor. Inhibition of GGDP synthase (GGDPS) is of interest from a drug development perspective as GGDPS inhibition results in impaired protein geranylgeranylation, which in multiple myeloma, disrupts monoclonal protein trafficking and induces apoptosis. We have recently reported on a series of isoprenoid triazole bisphosphonates and have demonstrated that a 3:1 mixture of homogeranyl and homoneryl isomers potently, and in a synergistic manner, inhibits GGDPS. We now present the synthesis and biological evaluation of a novel series of bishomoisoprenoid triazoles which furthers our understanding of the structure-function relationship of this class. These studies demonstrate the importance of chain length and olefin stereochemistry on inhibitory activity.

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Acid‐Catalyzed Ring Opening Reaction of Cyclopropyl Carbinols with Acetonitrile to Synthesize Amides

Zhou,

Wang,

Fan

et al. 2024

ChemistrySelect

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A one‐pot protocol for the synthesis of amides has been developed by employing acetonitrile as nitrogen source and solvent. The reaction undergoes ring‐opening of cyclopropyl carbinols and in situ formation of homoallylic carbocation, which reacts with acetonitrile to give desired products. The substrate of this reaction is widely applicable and the desired products are obtained in moderate to good yields.

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Stereoselective Synthesis of Homoneryl and Homogeranyl Triazole Bisphosphonates

Cited by 23 publications

References 31 publications

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase

Acid‐Catalyzed Ring Opening Reaction of Cyclopropyl Carbinols with Acetonitrile to Synthesize Amides

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