The use of phosphate bioisosteres in medicinal chemistry and chemical biology

Elliott, T. S. J.; Slowey, Aine; Ye, Yulin; Conway, Stuart J.

doi:10.1039/c2md20079a

Cited by 162 publications

(187 citation statements)

References 133 publications

(254 reference statements)

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“…Medicinal chemists have found a number of phosphate bioisosteres that are recognized by these pockets, but typically there is a considerable loss of binding affinity. 36 An alternative approach is to create phosphate prodrugs in which the phosphate is unveiled following intracellular metabolism by a suitable enzyme.…”

Section: +mentioning

confidence: 99%

Covalent Guanosine Mimetic Inhibitors of G12C KRAS

Xiong

Hunter³

et al. 2016

ACS Med. Chem. Lett.

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Ras proteins are members of a large family of GTPase enzymes that are commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, of mutant G12C RAS that forms a covalent bond with cysteine 12. Here we report exploration of the structure−activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1 as covalent G12C KRAS inhibitors. We report the discovery of difluoromethylene bisphosphonate analogues such as compound 11, which, despite exhibiting reduced efficiency as covalent G12C KRAS inhibitors, remove the liability of the hydrolytic instability of the diphosphate moiety present in SML-8-73-1 and provide the foundation for development of prodrugs to facilitate cellular uptake. The SAR and crystallographic results reaffirm the exquisite molecular recognition that exists in the diphosphate region of RAS for guanosine nucleotides which must be considered in the design of nucleotide-competitive inhibitors.

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Section: +mentioning

confidence: 99%

Covalent Guanosine Mimetic Inhibitors of G12C KRAS

Xiong

Hunter³

et al. 2016

ACS Med. Chem. Lett.

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“…Literature precedents have indicated that the sulphonyl bismethylene group has similar steric requirements to the phosphate group. Since these two groups differ in electronic characteristics, it may well be the ability of the phosphate group to bear a negative charge that is responsible for its contribution to the activity of PAF [243].…”

Section: Kitsonmentioning

confidence: 99%

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

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Molecular Metaphors is the application of squaryl building blocks towards creative functional group chemistry to produce lead compounds and imaging agents. This strategy is applied to rational drug design and to various imaging agents that would normally contain conventional functional group chemistry. These, include carboxylic acids, α-amino acids, peptide bonds and phosphonates. Moreover, the squaryl metaphor is a precursor to complex organic molecules involving functional group interchange (FGI) and rearrangements. This article discusses the application of these metaphors in the area of neurochemistry, especially NMDA receptors. An important area of drug design is the inhibition of angiotensin II enzyme by the use of losartan. This commercial drug contains a tetrazole moiety that can be modified using the squaryl group to give a semisquarate derivative. These concepts can extend to the semisquarate of ibuprofen. Moreover, a discussion on peptidomimetics regarding the substitution of the peptide bond for squaramide allows for a change in the biological properties due to modification at the peptide bond. Furthermore, the topic on how squaryl metaphors can be exploited primarily by the central 1,3-hydroxyamide sequence to the generation of a novel class of HIV protease inhibitors. Also, squaryl metaphors can be used to develop potential inhibitors of glutathione and novel anti-migraine drugs. The discussion continues on the design of anticancer drugs: in particular, a novel class of metalloproteases, including phosphonates for semisquaramides, leading to squaryl nucleosides. This review concludes with the application of squaryl metaphors in the design of positron emission tomography (PET) and magnetic resonance imaging (MRI) agents towards theranostics. describe the ability of individual functional chemical groups to mimic other moieties [2,3]. KeywordsErlenmeyer rationalised these concepts and categorised isosteres into atoms, ions and molecules based on the valence level of electrons [4]. A further understanding by Friedman led to the term bioisosterism to include all atoms and molecules that fit the broadest definition of isosteres [5]. This approach was independent of whether the drug was an agonist or an antagonist towards biological activity.Moreover, Thornber applied the term bioisosterism to include subunits, groups or molecules that possess physicochemical properties of similar biological effects [6]. Finally, in 1991 Burger widened the definition of bioisosteres to include compounds or groups that possess similar molecular shapes and volumes independent of agonists or antagonists [7]. REVIEW ARTICLE Squaryl KitsonThese bioisosteres would require approximately the same distribution of electrons and give a high probability of generating comparable physical properties such as hydrophobicity [8]. Currently, bioisosterism is one of the most useful tools to the medicinal chemist in rational drug design and in particular regarding the carboxylic acid bioisosteres [9]. The carboxylic acid functional ...

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“…Nucleotide analogues featuring methylenebisphosphonate linkage are especially interesting since they represent a versatile platform for the synthesis of enzyme inhibitors and important agents for anticancer and antiviral therapy. [1][2][3][4][5] Progress in the development of these species is closely linked with the development of a bioisostere concept whereby methylenebisphosphonates (H2O3P-CXY-PO3H2) are analogues of endogenous pyrophosphate (H2O3P-O-PO3H2). 6,7 During recent decades numerous fundamental researches were made on design and tactical application of phosphate and pyrophosphate isosteres.…”

Section: Introductionmentioning

confidence: 99%

Phosphonate analogues of nucleoside polyphosphates

Romanenko¹,

Kukhar²,

Zhdankin³

2017

Arkivoc

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This article provides an overview of the efforts toward the synthesis of nucleoside polyphosphate mimics featuring a P-CXY-P scaffold. The following synthetic approaches to these compounds are summarized: (i) nucleophilic displacement of 5´-O-tosyl nucleoside by the ammonium salts of methylenebisphosphonic acid; (ii) synthesis via activated phosphate/phosphonate substrates; (iii) Mitsunobu coupling between a nucleoside and methylenebisphosphonic acid; (iv) phosphorylation of a protected nucleoside under Yoshikawa's reaction conditions with methylenebis(phosphonic dichloride); (v) synthesis via nucleophilic cleavage of cyclic trimetaphosph(on)ates; (vi) enzyme-mediated reactions.

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The use of phosphate bioisosteres in medicinal chemistry and chemical biology

Cited by 162 publications

References 133 publications

Covalent Guanosine Mimetic Inhibitors of G12C KRAS

Covalent Guanosine Mimetic Inhibitors of G12C KRAS

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Phosphonate analogues of nucleoside polyphosphates

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