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Quality not Quantity: The Role of Marine Natural Products in Drug Discovery and Reverse Chemical Proteomics

View Article: PubMed Central

ABSTRACT

Reverse chemical proteomics combines affinity chromatography with phage display and promises to be a powerful new platform technology for the isolation of natural product receptors, facilitating the drug discovery process by rapidly linking biologically active small molecules to their cellular receptors and the receptors’ genes. In this paper we review chemical proteomics and reverse chemical proteomics and show how these techniques can add value to natural products research. We also report on techniques for the derivatisation of polystyrene microtitre plates with cleavable linkers and marine natural products that can be used in chemical proteomics or reverse chemical proteomics. Specifically, we have derivatised polystyrene with palau’amine and used reverse chemical proteomics to try and isolate the human receptors for this potent anticancer marine drug.

No MeSH data available.


Bromomethylation of PS microtitre plates via a Friedel-Crafts alkylation with bromomethyl methyl ether and tin(IV) bromide in sulfolane provides access to a wide range of different functionalisation, whilst maintaining the structural integrity and optical clarity of the plate [47].
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f5-marinedrugs-03-00036: Bromomethylation of PS microtitre plates via a Friedel-Crafts alkylation with bromomethyl methyl ether and tin(IV) bromide in sulfolane provides access to a wide range of different functionalisation, whilst maintaining the structural integrity and optical clarity of the plate [47].

Mentions: Although the nitration and oxidation methods were successful in attaching molecules to the surface of PS microtitre plates, they invariably caused some damage to the wells. Clark described a method of derivatising the surface of PS microtitre plates, whilst maintaining the structural integrity and optical clarity of the wells [47]. The method relies on an initial Friedel-Crafts alkylation of the plate with bromomethyl methyl ether and tin(IV) bromide in tetramethylene sulfone (sulfolane). The resulting bromomethylated PS, which is analogous to the chloromethylated Merrifield resin used for solid phase peptide synthesis [36], provides access to a wide range of functionality through subsequent nucleophilic displacement reactions (Fig. 5). Sulfolane is a polar aprotic solvent that is chemically and thermally stable, miscible with water and organic solvents, and does not damage PS. Therefore, it is an ideal solvent for performing many different reactions on the surface of PS plates, although its relatively high melting point (28 °C) introduces some difficulties in handling.


Quality not Quantity: The Role of Marine Natural Products in Drug Discovery and Reverse Chemical Proteomics
Bromomethylation of PS microtitre plates via a Friedel-Crafts alkylation with bromomethyl methyl ether and tin(IV) bromide in sulfolane provides access to a wide range of different functionalisation, whilst maintaining the structural integrity and optical clarity of the plate [47].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756327&req=5

f5-marinedrugs-03-00036: Bromomethylation of PS microtitre plates via a Friedel-Crafts alkylation with bromomethyl methyl ether and tin(IV) bromide in sulfolane provides access to a wide range of different functionalisation, whilst maintaining the structural integrity and optical clarity of the plate [47].
Mentions: Although the nitration and oxidation methods were successful in attaching molecules to the surface of PS microtitre plates, they invariably caused some damage to the wells. Clark described a method of derivatising the surface of PS microtitre plates, whilst maintaining the structural integrity and optical clarity of the wells [47]. The method relies on an initial Friedel-Crafts alkylation of the plate with bromomethyl methyl ether and tin(IV) bromide in tetramethylene sulfone (sulfolane). The resulting bromomethylated PS, which is analogous to the chloromethylated Merrifield resin used for solid phase peptide synthesis [36], provides access to a wide range of functionality through subsequent nucleophilic displacement reactions (Fig. 5). Sulfolane is a polar aprotic solvent that is chemically and thermally stable, miscible with water and organic solvents, and does not damage PS. Therefore, it is an ideal solvent for performing many different reactions on the surface of PS plates, although its relatively high melting point (28 °C) introduces some difficulties in handling.

View Article: PubMed Central

ABSTRACT

Reverse chemical proteomics combines affinity chromatography with phage display and promises to be a powerful new platform technology for the isolation of natural product receptors, facilitating the drug discovery process by rapidly linking biologically active small molecules to their cellular receptors and the receptors’ genes. In this paper we review chemical proteomics and reverse chemical proteomics and show how these techniques can add value to natural products research. We also report on techniques for the derivatisation of polystyrene microtitre plates with cleavable linkers and marine natural products that can be used in chemical proteomics or reverse chemical proteomics. Specifically, we have derivatised polystyrene with palau’amine and used reverse chemical proteomics to try and isolate the human receptors for this potent anticancer marine drug.

No MeSH data available.