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Linkers, spacers and cross-linkers
Cross-linking agents between two or more functional substances (e.g. fluorescent substances and proteins) that do not directly affect their activity are called spacers or linkers.
The properties of the linker, such as hydrophilicity, spacer length and mode of binding to the active site, have been shown to have a significant impact on overall performance. Maximising activity and performance can be achieved by selecting the appropriate linker.
Linkers are not limited to bio-related applications, but also apply to electronic materials and various fine materials.
Since its foundation, Shinsei Chemical has focused on the development of polyethylene glycol (PEG, PEO) derivatives as hydrophilic linkers. By changing the various functional groups at both ends and the length of the linker (ethylene glycol repeat unit), it can be used in a variety of applications.
Shinsei Chemical can also apply PEG, alkyl chains and other diols, as well as tailor-made cross-linkers and linkers combining several elements.
The following are some of the points to note for each linker.
Polyethylene glycol (PEG/PEO)
- Repeat unit: ethylene glycol（-CH2-CH2-O）-
- Stability:The ether bond does not break unless heated to high temperatures with strong acids or alkalis, but the terminal OH structure is unstable and breaks under relatively mild conditions, partially by-producing a short structure (stable after conversion of both ends to functional groups other than OH).
- Commercial availability of low molecular weightCommercial products with various functional groups at both ends are inexpensively available for relatively short structures (n=7: up to MW=308 in the linker part).
- Ease of obtaining polymer commercial products: mixtures of polymers obtained from the polymerisation reaction of ethylene oxide, separated in a rough molecular weight range, are available at low cost, even with a molecular weight of 10K (10,000) or more.
- Ease of synthesis of polymeric structures: we are proud to say that only Shinsei Chemistry can handle single structures without molecular weight distribution. n=220 (molecular weight approx. 9,700) is the longest so far, but please note that the longer the more expensive it becomes.
- Highly hydrophilic, good solubility in both water and organic solvents. Most commonly used linker.
- PEG is not only used as a spacer, but also used to improve water solubility.
- When the molecular weight exceeds about 500, commercial products based on the polymerisation method are available at low cost, but their quality varies due to molecular weight distribution. Our compounds are not synthesised by polymerisation and have a single structure with no molecular weight distribution.
- PEG page
- PEG derivatives list
Polypropylene glycol (polyoxetanes, PPG/PO)
- Repeat unit: propylene glycol（-CH2-CH2-CH2-O）-
- Stability:Does not decompose unless heated to high temperatures with strong acids or alkalis; it is more terminally stable than PEG and no by-production of short structures is observed.
- Commercial availability of low molecular weightGenerally difficult to obtain; n=2 in the OH-OH form is available but can be quite expensive.
- Ease of obtaining polymer commercial products:Hard to obtain
- Ease of synthesis of polymeric structures: Established up to n=14.If demand is anticipated, we would like to seriously tackle polymer synthesis.
Although it is not easy to prepare polymers by carbon-carbon bonding of alkyl chains, if oxygen (O) is allowed to be sandwiched between the alkyls, we can expect to produce a considerable number of single polymeric substances.
- Properties between those of PEG and alkyls; much more fat soluble than PEG.
- PPG derivatives list
Polybutylene glycol (poly-THF linear, PBG)
- Repeat unit:Butanediol（-CH2-CH2-CH2-CH2-O）-
- Stability:Like PPG, it does not decompose unless heated to high temperatures with strong acids and alkalis; it is more terminally stable than PEG and by-production of short structures is not detected.
- Commercial availability:Generally not commercially available.
- Ease of synthesis of polymeric structures:We have not synthesised poly-THF (cyclic ether) and larger than n=3, but the synthesis method is well established and if there is demand we would like to get serious about synthesising high molecular weight structures.
- Has properties between PEG and alkyl; it is even more fat-soluble than PPG and is closer to the alkyl structure.
- Structures with an increased number of methylene (e.g. pentanediol and hexanediol polyethers) are also available, although they have not been synthesised.
- PBG derivatives list
Combination of carbonate (carbonate ester) bonds and PEG.
- Repeat unit:Carbonate bond of triethylene glycol.（-PEG3-OCO）-
- Stability:Acid-resistant, easily hydrolysed and decarboxylated by alkalis. Stability comparable to that of esters.
- Commercial availability:No commercial products available
- Ease of synthesis of polymeric structures:Relatively easy to deal with.
- Not related to polycarbonate (carbonate polymer of bisphenol A), which is commonly distributed.
- The nature of the carbonate moiety (acid-resistant and hydrolysed by alkalis) makes it slightly different to PEG in terms of use.
- The example shown here is triethylene glycol (PEG3), but structures of any length, such as PEGn, PPG and PBG, are also applicable.
- Polycarbonates list
Combination of amide bonding and PEG.
- Repeat unit:Elongation of oligoethylene glycol by amide bonding.-（PEG5-CONH）-
- Stability:Equivalent to general amide bonds. Cannot be broken unless heated with a very strong acid or alkali.
- Commercial availability of high molecular weight:Even relatively short structures are hard to find and hard to obtain commercially.
- Ease of synthesis of polymeric structures:Our extensive experience in peptide synthesis enables us to synthesise macromolecules in a short time.
- The example shown here is an oligomer of pentaethylene glycol (PEG5), but it can be used for PEGn, PPGn and alkyls of any length.
- The repeated reaction of amide bonds, which is simpler and higher yielding than ether bonds, allows the synthesis of hydrophilic polymeric linkers similar to PEG in a short time.
- Low-polarity polymer linkers can be synthesised in a short time if alkylamino acids are used instead of PEG.
- The asymmetrical structure(NH2-COOH) makes it easier to control selective responses at both ends.
- NHR-PEGn-COOR list
Alkyl chain
- Repeat unit:Methylene(-CH2)-
- Stability:Stability is the strongest. There is no risk of the linker part breaking off.
- Commercial availability of low molecular weight:Relatively short structures (n=18: up to about MW=252 for the linker part) are available commercially with various functional groups at both ends at relatively low cost.
- Commercial availability of high molecular weight:No commercial products are found above n=20.
- Ease of synthesis of polymeric structures:It is possible to do this by making full use of C-C bond reactions such as Wittig, but the higher the polymer, the more difficult it is expected to be to purify because of its extremely low polarity, and it is very expensive.
- As n increases, commercial starting materials may contain branching structures as impurities, which are very difficult to remove.
- Extending the repetition unit n is not easy。
- Highly hydrophobic and its water solubility decreases significantly with increasing n. In aqueous systems, it is said to no longer serve as a linker due to aggregation caused by hydrophobic bonds. Its property of easily entering lipid-soluble phospholipids is also used in many applications.
PEG-related technical documents
- Mono-disperse polyethylene glycols(TD001)
- PEG hybrid compounds(TD025)
- PEG linker that can be cleaved under mild conditions(TD030)(not ready)
- macrocyclic crown ether(TD034)
- Fluorescently labelled PEG molecular weight markers(TD036)
- Crown ether with branches(TD037)
- About the nomenclature of polyethylene glycol (PEG) derivatives(TD039)(written in Japanese)
- Cyclodextrins with PEG linkers(TD042)
- Synthesis of dyes with PEG linkers and fluorescent dyes(TD048)
- Functionalisation of each end of PEG Linker(TD049)
- Spacers and cross-linkers(TD050)
- PEG dicarboxylic acid derived from commercial PEG(TD054)
- Diamino PEG derived from commercial PEG(TD055)
- HaloTag HaloLinker (HaloTag HaloLinker)(TD066)
- List of PEG derivatives
- List of fluorescently labelled PEG derivatives
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