Efforts toward elucidating Thalidomide’s molecular target: an expedient synthesis of the first Thalidomide biotin analogue

Abstract

Herein we describe the synthesis of the first Thalidomide-biotin analogue in order to initiate investigations into the unknown molecular mode of action of Thalidomide. In this manner we describe the attachment of biotin tether through the Huisgen 1,3-dipolar cycloaddition or "click" synthetic methodology.

Synthesis of Biotinylated Episilvestrol: Highly Selective Targeting of the Translation Factors eIF4AI/II

“…Incorporation of a terminal alkyne in amide 7 enabled biotinylation of 2 via a Huisgen 1,3-dipolar cycloaddition reaction (Scheme ) . The biotin linker 8 was synthesized following a modified procedure . Cycloaddition in the presence of tris(benzyltriazolylmethyl)amine (TBTA) as a Cu(I) ligand gave biotinylated episilvestrol 9 in a good yield.…”

Synthetic Access to the Mandelalide Family of Macrolides: Development of an Anion Relay Chemistry Strategy

“…This particularly important observation holds promise for the future determinations of the mandelalide cellular binding target by functionalization of the 24-OH with a chemical probe. To this end, two mandelalide analogs possessing alkyne and biotin probes were prepared, the latter via attachment of a biotin tether 44 via a Huisgen 1,3-dipolar cycloaddition 45 to the derived acetylenic ester (−)- 82 (Scheme 15). The polyethylene glycol (PEG) unit in turn was employed as a linker molecule between biotin and mandelalide A to increase solubility of the overall molecule in water.…”

E3 ligase ligand chemistries: from building blocks to protein degraders

“…A variety of thalidomide derivatives were synthesised in which the imide nitrogen of thalidomide was utilised for modifications. 81,82 However, due to the expected lack of CRBN binding, such conversions are not discussed in detail. As mentioned above, the imide nitrogen can be equipped with a Boc protecting group, 83 which was utilised to avoid side-products when alkylating the phenolic group of compound 25 during the synthesis of Example 13 (Scheme 4).…”