Design and Synthesis of N-Maleimido-Functionalized Hydrophilic Polymers via Copper-Mediated Living Radical Polymerization: A Suitable Alternative to PEGylation Chemistry
摘要:
A series of a-functional maleimide polymethacrylates (M-n = 4.1-35.4 kDa, PDi = 1.06-1.27) have been prepared via copper-catalyzed living radical polymerization (LRP). Two independent synthetic protocols have been successfully developed and the polymers obtained in multigram scale, with an 80-100% content of maleimide reactive chain ends, depending on the method employed. A method for the synthesis of amino-terminated polymers, starting from Boc-protected amino initiators, has also been developed, as these derivatives are key intermediates in one of the two processes studied in the present work. The alternative synthetic pathway involves an initiator containing a maleimide unit "protected" as a Diels-Alder adduct. After the polymerization step, the maleimide functionality has been reintroduced by retro-Diels -Alder reaction, by simply refluxing those polymers in toluene for 7 h. These maleimido-terminated materials, poly(methoxyPEG((475))) methacrylates and poly(glycerol) methacrylates, differ for both the nature and size of the polymer side branches and showed an excellent solubility in water, a property that made them an ideal candidate for the synthesis of new polymer- (poly) peptide biomaterials. These functional polymers have been successfully employed in conjugation reactions in the presence of thiol-containing model substrates, namely, reduced glutathione (gamma-Glu-Cys-Gly) and the carrier protein, bovine serum albumin (BSA), in 100 mM phosphate buffer (pH 6.8-7.4) and ambient temperature.
The application provides a method of producing a comb polymer comprising the steps of:
(a) Providing:
(i) a plurality of monomers which are linear, branched or star-shaped, substituted or non-substituted, and have an olefinically unsaturated moiety, the olefinically unsaturated moiety being capable of undergoing addition polymerisation;
(ii) an initiator compound; the initiator compound comprising a homolytically cleavable bond.
(iii) a catalyst capable of catalysing the polymerisation of the monomer; and
(b) Causing the catalyst to catalyse, in combination with the initiator, the polymerisation of a plurality of the monomers to produce the comb polymer.
Catalysts and polymers obtainable by the process are also provided.
Preferably, the comb polymer is capable of binding proteins and may be produced from monomers which are alkoxy polyethers, such as poly(alkyleneglycol) or polytetrahydrofuran.
The application provides a method of producing a comb polymer comprising the steps of:
(a) Providing:
(i) a plurality of monomers which are linear, branched or star-shaped, substituted or non-substituted, and have an olefinically unsaturated moiety, the olefinically unsaturated moiety being capable of undergoing addition polymerisation;
(ii) an initiator compound; the initiator compound comprising a homolytically cleavable bond.
(iii) a catalyst capable of catalysing the polymerisation of the monomer; and
(b) Causing the catalyst to catalyse, in combination with the initiator, the polymerisation of a plurality of the monomers to produce the comb polymer.
Catalysts and polymers obtainable by the process are also provided.
Preferably, the comb polymer is capable of binding proteins and may be produced from monomers which are alkoxy polyethers, such as poly(alkyleneglycol) or polytetrahydrofuran.
LIVING RADICAL POLYMERIZATION INITIATOR COMPRISING A FUNCTIONAL GROUP CAPABLE OF REACTING WITH POLYEPTIDES OR THE LIKE, COMB POLYMER OBTAINED THEREWITH , POLYPEPTIDE CONJUGATES AND DRUGS OBTAINED THEREFROM.
申请人:Warwick Effect Polymers Limited
公开号:EP1784430A1
公开(公告)日:2007-05-16
POLYMERS
申请人:Haddleton David M.
公开号:US20090082224A1
公开(公告)日:2009-03-26
The application discloses a process for making a polymer having pendant side groups comprising:
(i) polymerising an olefinically unsaturated monomer functionalised with (a) an azide group optionally protected by a protecting group, or (b) an alkyne group optionally protected by a protecting group, by living radical polymerisation, most preferably RAFT, transitional metal mediated living radical polymerisation (TMM-LRP) and/or atom transfer radical polymerisation, to produce a polymer intermediate;
(ii) removing, when present, at least a portion of the total number of protecting groups from the polymer intermediate;
(iii) reacting the polymer intermediate with at least one pendant side group moiety functionalised with (a) an alkyne group or (b) an azide group respectively so that the alkyne and azide groups react to attach the pendant side group to the polymer.
Processes for making supports comprising pendant side groups, and polymers and supports prepared by the method are also disclosed.