Phosphonate and bisphosphonate analogues of farnesyl pyrophosphate as potential inhibitors of farnesyl protein transferase

Holstein, Sarah A.; Cermak, Diana M.; Wiemer, David F.; Lewis, Kriste A.; Hohl, Raymond J.

doi:10.1016/s0968-0896(98)00034-0

Cited by 93 publications

(69 citation statements)

References 33 publications

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“…As a final part of these investigations we tested the efficacy of the developed cross-coupling method in the synthesis of more complex arylphosphonate dies-A C H T U N G T R E N N U N G ters ( Table 5) that are of potential importance to medicinal chemistry [10,35] and nucleic acids-based therapeutics. [13,15,36] In entry 1 (Table 5), a protected tyrosine triflate derivative 4 in the reaction with diethyl H-phosphonate was successfully converted into the corresponding arylphosphonate 9 in high yield.…”

Section: Synthesis Of Arylphosphonate Diesters Promoted By the Acetatmentioning

confidence: 99%

Preparation of Arylphosphonates by Palladium(0)‐Catalyzed Cross‐Coupling in the Presence of Acetate Additives: Synthetic and Mechanistic Studies

Kalek¹,

Jezowska²,

Stawiński³

2009

Adv Synth Catal

147

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An efficient protocol for the synthesis of arylphosphonate diesters via a palladium-catalyzed cross-coupling of H-phosphonate diesters with aryl electrophiles, promoted by acetate ions, was developed. A significant shortening of the cross-coupling time in the presence of the added acetate ions was achieved for bidentate and monodentate supporting ligands, and for different aryl electrophiles (iodo, bromo and triflate derivatives). The reaction conditions were optimized in terms of amount of the catalyst, supporting ligands, and source of the acetate ion used. Various arylphosphonates, including those of potential biological significance, were synthesized using this newly developed protocol. Some mechanistic aspects of the investigated reactions are also discussed.

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Section: Synthesis Of Arylphosphonate Diesters Promoted By the Acetatmentioning

confidence: 99%

Preparation of Arylphosphonates by Palladium(0)‐Catalyzed Cross‐Coupling in the Presence of Acetate Additives: Synthetic and Mechanistic Studies

Kalek¹,

Jezowska²,

Stawiński³

2009

Adv Synth Catal

147

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“…Some nitrogen-containing BPs can also inhibit squalene synthase (17,18), which is involved in the synthesis of cholesterol and also uses FPP as a substrate. Furthermore, a recent study has demonstrated that certain bisphosphonate analogues of FPP are able to inhibit FTase (19).…”

mentioning

confidence: 99%

Identification of a Novel Phosphonocarboxylate Inhibitor of Rab Geranylgeranyl Transferase That Specifically Prevents Rab Prenylation in Osteoclasts and Macrophages

Coxon

Helfrich²,

Larijani

et al. 2001

Journal of Biological Chemistry

159

162

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Nitrogen-containing bisphosphonate drugs inhibit bone resorption by inhibiting FPP synthase and thereby preventing the synthesis of isoprenoid lipids required for protein prenylation in bone-resorbing osteoclasts. NE10790 is a phosphonocarboxylate analogue of the potent bisphosphonate risedronate and is a weak antiresorptive agent. Although NE10790 was a poor inhibitor of FPP synthase, it did inhibit prenylation in J774 macrophages and osteoclasts, but only of proteins of molecular mass ϳ22-26 kDa, the prenylation of which was not affected by peptidomimetic inhibitors of either farnesyl transferase (FTI-277) or geranylgeranyl transferase I (GGTI-298). These 22-26-kDa proteins were shown to be geranylgeranylated by labelling J774 cells with [ 3 H]geranylgeraniol. Furthermore, NE10790 inhibited incorporation of [ 14 C]mevalonic acid into Rab6, but not into H-Ras or Rap1, proteins that are modified by FTase and GGTase I, respectively. These data demonstrate that NE10790 selectively prevents Rab prenylation in intact cells. In accord, NE10790 inhibited the activity of recombinant Rab GGTase in vitro, but did not affect the activity of recombinant FTase or GGTase I. NE10790 therefore appears to be the first specific inhibitor of Rab GGTase to be identified. In contrast to risedronate, NE10790 inhibited bone resorption in vitro without markedly affecting osteoclast number or the F-actin "ring" structure in polarized osteoclasts. However, NE10790 did alter osteoclast morphology, causing the formation of large intracellular vacuoles and protrusion of the basolateral membrane into large, "domed" structures that lacked microvilli. The anti-resorptive activity of NE10790 is thus likely due to disruption of Rabdependent intracellular membrane trafficking in osteoclasts.

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“…Squalene synthase (36) is another potential target, since ergosterol (at low levels) is required for cell proliferation (8) and a T. cruzi squalene synthase is inhibited by lipophilic bisphosphonates (36). Also, some lipophilic bisphosphonates tar- get farnesyl protein transferases (37). Additional evidence for FPPS as at least one target-in addition to the observed TbFPPS inhibition in vitro-is that bisphosphonate inhibition of T. brucei cell growth is rescued by addition of FPP (13), which would not be the case for long-chain prenyl synthase or squalene synthase inhibition.…”

Section: Resultsmentioning

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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Phosphonate and bisphosphonate analogues of farnesyl pyrophosphate as potential inhibitors of farnesyl protein transferase

Cited by 93 publications

References 33 publications

Preparation of Arylphosphonates by Palladium(0)‐Catalyzed Cross‐Coupling in the Presence of Acetate Additives: Synthetic and Mechanistic Studies

Preparation of Arylphosphonates by Palladium(0)‐Catalyzed Cross‐Coupling in the Presence of Acetate Additives: Synthetic and Mechanistic Studies

Identification of a Novel Phosphonocarboxylate Inhibitor of Rab Geranylgeranyl Transferase That Specifically Prevents Rab Prenylation in Osteoclasts and Macrophages

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

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