Phosphinato(dialkylmethyl)phosphonates as pyrophosphate mimics: synthesis and squalene synthetase inhibitory activity of farnesyl phosphinato(dialkylmethyl)phosphonates

Prashad, Mahavir; Tomesch, J. C.; Wareing, JR; Scallen, Terence J.

doi:10.1016/0223-5234(93)90022-7

Cited by 12 publications

(3 citation statements)

References 9 publications

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“…These isosteric moieties were chosen bearing in mind previous studies on isosters of the diphosphate group of prenyl diphosphates as squalene synthase (25), protein:farnesyl transferase (47), and protein: geranylgeranyl transferase inhibitors (48,49). Compounds 1-3 had no effect on either the Z-FPP synthase or the E-FPP synthase (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Purification, Enzymatic Characterization, and Inhibition of theZ-Farnesyl Diphosphate Synthase from Mycobacterium tuberculosis

Schulbach

Mahapatra

Macchia

et al. 2001

Journal of Biological Chemistry

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We have recently shown that open reading frame Rv1086 of the Mycobacterium tuberculosis H37Rv genome sequence encodes a unique isoprenyl diphosphate synthase. The product of this enzyme, ,E,Z-farnesyl diphosphate, is an intermediate for the synthesis of decaprenyl phosphate, which has a central role in the biosynthesis of most features of the mycobacterial cell wall, including peptidoglycan, arabinan, linker unit galactan, and lipoarabinomannan. We have now purified Z-farnesyl diphosphate synthase to near homogeneity using a novel mycobacterial expression system. Z-Farnesyl diphosphate synthase catalyzed the addition of isopentenyl diphosphate to ,E-geranyl diphosphate or ,Zneryl diphosphate yielding ,E,Z-farnesyl diphosphate and ,Z,Z-farnesyl diphosphate, respectively. The enzyme has an absolute requirement for a divalent cation, an optimal pH range of 7-8, and K m values of 124 M for isopentenyl diphosphate, 38 M for geranyl diphosphate, and 16 M for neryl diphosphate. Inhibitors of the Zfarnesyl diphosphate synthase were designed and chemically synthesized as stable analogs of ,E-geranyl diphosphate in which the labile diphosphate moiety was replaced with stable moieties. Studies with these compounds revealed that the active site of Z-farnesyl diphosphate synthase differs substantially from E-farnesyl diphosphate synthase from pig brain (Sus scrofa).Isoprenyl diphosphate synthases catalyze the condensation of an allylic diphosphate with isopentenyl diphosphate (IPP, 1 C 5 ) via an electrophilic alkylation reaction to produce longer allylic diphosphates (1, 2). Chain elongation continues until a physiologically appropriate chain length is reached, at which time the molecule may undergo further modifications (dephosphorylation, cyclization, or head-to-head condensation reactions). Polyprenyl phosphate (Pol-P) is formed by dephosphorylation of an allylic prenyl diphosphate chain. The predominant form of prokaryotic Pol-P is ,diE,polyZ-undecaprenyl phosphate 2 (C 55 ); however, there are documented exceptions in Paracoccus denitrificans (3) and in Mycobacterium sp. (4 -8). M. smegmatis contains heptaprenyl diphosphate (8) (C 35 , four saturated, three Z double bonds) and decaprenyl diphosphate (5) (C 50 , , one E, and eight Z double bonds), whereas M. tuberculosis contains only decaprenyl phosphate (6). Although the stereochemistry of decaprenyl phosphate from M. tuberculosis has not been determined, our enzymatic studies suggest that it has similar stereochemistry to decaprenyl phosphate from M. smegmatis (9).Pol-P is central to prokaryotic cell wall synthesis as a sugar carrier, and it has been reported that the levels of Pol-P may be rate-limiting for in vivo cell wall synthesis (10 -13). Our laboratory has shown that Pol-P is instrumental in the synthesis of each component of the covalently linked peptidoglycan-arabinogalactan-mycolic acid cell wall core of mycobacteria, and other noncovalently associated macromolecules such as lipomannan and lipoarabinomannan (5,14,15). The importance of Pol-P is also demons...

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Section: Discussionmentioning

confidence: 99%

Purification, Enzymatic Characterization, and Inhibition of theZ-Farnesyl Diphosphate Synthase from Mycobacterium tuberculosis

Schulbach

Mahapatra

Macchia

et al. 2001

Journal of Biological Chemistry

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“…254 A novel radiometric assay for SQS activity, intended for development of new inhibitors, has been described 255 and an improved method for analysis and purification of the FPP substrate has been reported. 256 The most important new SQS inhibitors to be discovered are the bisphosphonates (18 and other isomeric long chain alkyl phosphates), [257][258][259][260][261][262][263] which are thought to mimic the FPP substrate, and the zaragozic acids 264 (ZGAs, squalestatins [265][266][267][268] ), polyketide 269,270 fungal metabolites which are active at nano-to pico-molar concentrations 271,272 and may mimic the reaction intermediate PSPP. ZGAs A (squalestatin 1; 19), 273,274 B (20), C (21) 275 and D ( 22) 276 share a polar 2,8-dioxabicyclo[3.2.1]octane-4,6,7-trihydroxy-3,4,5tricarboxylic acid core and vary in the composition of the lipophillic 6-O-acyl and 1-alkyl side-chains.…”

Section: Biosynthesis Of Squalene Epoxide From Isopentenyl Pyrophosphatementioning

confidence: 99%

The biosynthesis of steroids and triterpenoids

Brown¹

1998

Nat. Prod. Rep.

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“…Compound 6 was prepared as shown in Scheme 3. Compound 16 [17] was deprotonated on the terminal methyl portion by using n-butyllithium and then alkylated with bromide 12 to give the intermediate 17. Subsequent hydrolysis of the ethyl phosphonate group was carried out by initial treatment with bromotrimethylsilane and 2,4,6-collidine followed by aqueous potassium hydroxide to give compound 6 as the potassium salt.…”

Section: Chemical Synthesismentioning

confidence: 99%

Synthesis of Stable Analogues of Geranylgeranyl Diphosphate Possessing a (Z,E,E)‐Geranylgeranyl Side Chain, Docking Analysis, and Biological Assays for Prenyl Protein Transferase Inhibition

et al. 2006

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Herein, we report the synthesis of novel stable analogues of geranylgeranyl diphosphate (GGPP), in which the "natural" all-trans geranylgeranyl portion has been replaced by a (Z,E,E)-geranylgeranyl chain. The change in configuration and consequent change in the relative position of the polar portion with the lipophilic side chain did not improve the properties of the E,E,E analogues in their inhibition of geranylgeranyl protein transferase I (GGTase I). However, a significant level of GGTase I inhibition and selectivity for GGTase I over farnesyl transferase (FTase) was maintained the unsubstituted phosphonoacetamidoxy derivative 4 a. This has shed light on the relative importance of the configuration at the C2=C3 double bond among GGPP derivatives. Moreover, the biological activities of all the compounds reported herein, in particular the preferential FTase inhibitory activity shown by compound 6, were in good agreement with the results of docking analysis.

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Phosphinato(dialkylmethyl)phosphonates as pyrophosphate mimics: synthesis and squalene synthetase inhibitory activity of farnesyl phosphinato(dialkylmethyl)phosphonates

Cited by 12 publications

References 9 publications

Purification, Enzymatic Characterization, and Inhibition of theZ-Farnesyl Diphosphate Synthase from Mycobacterium tuberculosis

Purification, Enzymatic Characterization, and Inhibition of theZ-Farnesyl Diphosphate Synthase from Mycobacterium tuberculosis

The biosynthesis of steroids and triterpenoids

Synthesis of Stable Analogues of Geranylgeranyl Diphosphate Possessing a (Z,E,E)‐Geranylgeranyl Side Chain, Docking Analysis, and Biological Assays for Prenyl Protein Transferase Inhibition

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