Pyridinium-1-yl Bisphosphonates Are Potent Inhibitors of Farnesyl Diphosphate Synthase and Bone Resorption

Sanders, John M.; Song, Yuanlin; Chan, Julian M. W.; Zhang, Yonghui; Jennings, Sydney; Kosztowski, Thomas; Odeh, Sarah; Flessner, Ryan M.; Schwerdtfeger, Christine A.; Kotsikorou, Evangelia; Meints, Gary A.; Gómez, Aurora Ortiz; González-Pacanowska, Dolores; Raker, Amy M.; Wang, Hong; Beek, Ermond R. van; Papapoulos, Socrates E.; Morita, Craig T.; Oldfield, Eric

doi:10.1021/jm040209d

Cited by 76 publications

(83 citation statements)

References 48 publications

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“…In order to better understand the activities of the different bisphosphonates in vitro and in vivo, we determined their IC 50 s against three different drug targets, a Plasmodium vivax GGPPS (PvGGPPS) (using GPP and FPP as substrates), human FPPS (HsFPPS), and human GGPPS (HsGGPPS), using the methods described previously (12,15,21,22). Results are shown in Table 4.…”

Section: Growth Inhibition Of P Berghei Eefs In Vitromentioning

confidence: 99%

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Lipophilic Bisphosphonates Are Potent Inhibitors of Plasmodium Liver-Stage Growth

Singh

Zhang

et al. 2010

Antimicrob Agents Chemother

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Nitrogen-containing bisphosphonates, drugs used to treat bone resorption diseases, also have activity against a broad range of protists, including blood-stage Plasmodium spp. Here, we show that newgeneration "lipophilic" bisphosphonates designed as anticancer agents that block protein prenylation also have potent activity against Plasmodium liver stages, with a high (>100) therapeutic index. Treatment of mice with the bisphosphonate BPH-715 and challenge with Plasmodium berghei sporozoites revealed complete protection (no blood-stage parasites after 28 days). There was also activity against blood-stage forms in vitro and a 4-day delay in the prepatent period in vivo. The lipophilic bisphosphonates have activity against a Plasmodium geranylgeranyl diphosphate synthase (GGPPS), as well as low nM activity against human farnesyl and geranylgeranyl diphosphate synthases. The most active inhibitor in vitro and in vivo had enzyme inhibitory activity similar to that of the other, less active compounds but was more lipophilic. Lipophilic bisphosphonates are thus promising leads for novel antimalarials that target liver-stage infection.

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Section: Growth Inhibition Of P Berghei Eefs In Vitromentioning

confidence: 99%

“…We used exactly the same methods described previously (12,15,22) for PvGGPPS, HsFPPS, and HsGGPPS expression, purification, and inhibition.…”

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confidence: 99%

Lipophilic Bisphosphonates Are Potent Inhibitors of Plasmodium Liver-Stage Growth

Singh

Zhang

et al. 2010

Antimicrob Agents Chemother

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“…Key compounds 4 to 59 were from batches whose syntheses and characterization were described previously (17)(18)(19)(20)(21)(22)(23). The compounds were Ն95% pure, as determined by elemental or analytical highperformance liquid chromatography-mass spectrometry (HPLC-MS) analysis, and they were also characterized by 1 H nuclear magnetic resonance (NMR) and high-resolution MS (HRMS).…”

Section: Methodsmentioning

confidence: 99%

In Vitro and In Vivo Investigation of the Inhibition of Trypanosoma brucei Cell Growth by Lipophilic Bisphosphonates

Yang

Zhu

Kim

et al. 2015

Antimicrob Agents Chemother

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dWe report the results of a screen of a library of 925 potential prenyl synthase inhibitors against Trypanosoma brucei farnesyl diphosphate synthase (TbFPPS) and against T. brucei, the causative agent of human African trypanosomiasis. The most potent compounds were lipophilic analogs of the bone resorption drug zoledronate, some of which had submicromolar to low micromolar activity against bloodstream form T. brucei and selectivity indices of up to ϳ300. We evaluated the effects of two such inhibitors on survival and parasitemia in a T. brucei mouse model of infection and found that survival increased by up to 16 days. We also investigated the binding of three lipophilic bisphosphonates to an expressed TbFPPS using crystallography and investigated the thermodynamics of binding using isothermal titration calorimetry.

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“…BPs are drugs that can inhibit bone resorption by reducing the number and activity of osteoclasts, thus they are essential components of multiple myeloma therapy for minimizing skeletal morbidity [14]. Moreover, BPs can act as carriers for drugs and can be easily adsorbed onto bone surface [15][16][17][18].…”

Section: Drug Targeting Of Platinum Drugs By (Bis)phosphonate Carriermentioning

confidence: 99%

Silica xerogels and hydroxyapatite nanocrystals for the local delivery of platinum–bisphosphonate complexes in the treatment of bone tumors: A mini-review

Iafisco

Margiotta

2012

Journal of Inorganic Biochemistry

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Pyridinium-1-yl Bisphosphonates Are Potent Inhibitors of Farnesyl Diphosphate Synthase and Bone Resorption

Cited by 76 publications

References 48 publications

Lipophilic Bisphosphonates Are Potent Inhibitors of Plasmodium Liver-Stage Growth

Lipophilic Bisphosphonates Are Potent Inhibitors of Plasmodium Liver-Stage Growth

In Vitro and In Vivo Investigation of the Inhibition of Trypanosoma brucei Cell Growth by Lipophilic Bisphosphonates

Silica xerogels and hydroxyapatite nanocrystals for the local delivery of platinum–bisphosphonate complexes in the treatment of bone tumors: A mini-review

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