Diversity linker

A library of fe(6-chloro-2-methoxyacridin-9-yl) and fe(7-chloro-2-met-hoxybenzo[Z>][l,5]naphthyridin-10-yl) analogs was synthesized to explore the effect of structurally diverse linkers on PrPSe replication in scrapie-infected neuroblastoma cells (2003MI4). 

As the linker units described above have become ever more elaborate and sophisticated, they have evolved into multifunctional (or diversity) linker units. Multifunctional linker imits use the cleavage step in solid-phase organic synthesis for incorporation of additional diversity into compound libraries, and the main classes of such linker units wiU be discussed in this section, along with representative cleavage strategies. 

Triazene Linker Units. Owing to their multifunctionality and high stability, triazene linker units have become the most versatile diversity linker units reported to date. Initial reports of triazene linker units appeared in the mid-1990s from the groups of both Moore " and Tour. Inspired by this work, the chemistry has been refined by Erase, whose T1 and T2 triazene linker units have now been extensively developed for multifunctional cleavage. 

DIVERSITY LINKER UNITS IN SOLID-PHASE ORGANIC SYNTHESIS... 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

The development of diversification linkers allows introduction of an additional element of diversity. Upon completion of the synthesis sequence, the linker is activated facilitating nucleophilic release of the library members from support In the ideal case, as implemented with the acylsulfonamide linker (Scheme 4a), the activated linker is sufficiently reactive that limiting amounts of nucleophile may be added to provide pure product after resin filtration.181 Diversification linkers have been developed for the preparation of carboxylic acid derivatives (Scheme 4a), amines (Scheme 4b),191 aromatic (Scheme 4c) and even heteroaromatic compounds (Scheme 4d).1101... 

Jin J, Cai Y, Li B, Conaway RC, Workman JL, Conaway JW, Kusch T (2005) In and out histone variant exchange in chromatin. Trends Biochem Sci 30 680-687 Khochbin S (2001) Histone HI diversity bridging regulatory signals to linker histone function. Gene 271 1-12... 

A linker originally designed for solid-phase synthesis of peptides is the backbone amide linker (11) (BAL), this anchoring approach has now been extended to the combinatorial synthesis of diverse amide [31], hydroxamate [32], oligosaccharide [33] and heterocyclic small molecule libraries [34-36]. 

Triazenes are disguised diazonium ions which can be released under very mild acidic conditions. Inspired by the use of triazenes in natural product synthesis by Nicolaou et al. [127] and the pioneering work of Moore et al. [128, 129] and Tour et al. [130] in the synthesis of triazenes on a solid support and the final detachment to give iodoarenes, a whole set of triazene-based linkers has been developed (Tab. 3.10) [131]. The arene diazonium salts generated from the triazene linkers offer diverse opportunities for multifunctional cleavage. Two linkers based on tria-... 

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