Synthesis and evaluation of KX-01 analogs with an exploration of linker attachment points for antibody-drug conjugates
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Linker
Conjugate
Antibody-drug conjugate
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Amide
Structure–activity relationship
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Abstract Benzalcyanoacetamides were designed and synthesized as reversible thiol conjugate addition acceptors. These thia‐conjugate additions can rapidly and reversibly achieve equilibrium under aqueous conditions at neutral pH. Kinetic studies show that electron‐withdrawing groups at the 4‐position of the phenyl ring of the benzalcyanoacetamides promote the conjugate addition at equilibrium. Dynamic thiol exchange of these conjugate acceptors is faster than singly activated α,β‐unsaturated carbonyl compounds. These thia‐conjugate additions can be assembled as potentially useful components in dynamic combinatorial chemistry.
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Thiol
Aqueous medium
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Silyl ether chemistry was used as the linker for an antibody drug conjugate to release a chemotherapeutic at low pH.
Linker
Conjugate
Antibody-drug conjugate
Silyl ether
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Antibody-drug conjugates offer the possibility of directing powerful cytotoxic agents to a malignant tumor while sparing normal tissue. The challenge is to select an antibody target expressed exclusively or at highly elevated levels on the surface of tumor cells and either not all or at low levels on normal cells. The current review explores 78 targets that have been explored as antibody-drug conjugate targets. Some of these targets have been abandoned, 9 or more are the targets of FDA-approved drugs, and most remain active clinical interest. Antibody-drug conjugates require potent cytotoxic drug payloads, several of these small molecules are discussed, as are the linkers between the protein component and small molecule components of the conjugates. Finally, conclusions regarding the elements for the successful antibody-drug conjugate are discussed.
Conjugate
Antibody-drug conjugate
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The synthesis of a linker derived from the 2-(trimethylsilylethoxy)methyl (SEM) protection group is described. This linker is particularly useful for the immobilization of steroids on solid phases, because the linker is robust but allows the substrates to be cleaved from the solid phase by fluoridolysis. The use of the linker is demonstrated by the coupling and cleavage of eight different steroids. Furthermore, two palladium coupling reactions are shown, whereby the steroidal vinyl triflates are attached to the solid phase via this linker.
Linker
Solid-Phase Synthesis
Cleavage (geology)
Trimethylsilyl
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Synthesis and applications of two new nonacid degradable linkers as an alternative to the Wang linker for solid-phase synthesis are described. Resin from linker 2 looks superior to linker 1 in terms of yields for both anchoring of the first building block and cleavage and in terms of higher purity of the final product. Use of linker 2 avoids side reactions associated with the use of Wang resin due to an undesired cleavage during final acid treatment.
Linker
Cleavage (geology)
Solid-Phase Synthesis
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Conjugate
Antibody-drug conjugate
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Linker
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Linker
Moiety
Carbon chain
Chain (unit)
Cholestane
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Linker
Moiety
Carbon chain
Chain (unit)
Cholestane
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Fusion protein was a genetic expression product, which was composed by two or more head-to-tail ligation genic coding region that were controlled by the same regulatory sequence. The design of linker played an important part in the fusion protein with connecting peptide. Linker designing, linker construction, linker classify, the function of linker, the problem arised and solved in the fusion protein with linker, were reviewed in this article.
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