Linker substitution

Chitosan, derived from crab shell chitin, is —80% deacetylated. It is dissolved in 1 M HO Ac (5 g/L) and freeze dried to yield a white, soft material. The chitosan is washed with 0.9 M A-methylmorpholine (NMM) in DMF followed by DMF. The Rink linker (0.4 mmol) is dissolved in 6 mL of DMF containing N-[(17/-benzotriazol-1 -yl)(dimethylamino)methylene]-A-methyl-methanaminium tetrafluoroborate A-oxide (TBTU) (0.3 M), HOBt (0.3 M), and NMM (0.4 M) and added to 150 mg (dry weight) of chitosan. The mixture is incubated at 45°C for 1 h, washed with DMF, and the chitosan capped with acetic anhydride-dry pyridine (1 1, v/v) for 1 h at 45°C. This procedure yields Fmoc-linker substituted chitin (Fig. 16). After drying in vacuo, the degree of substitution is determined by measuring the Fmoc released after treatment of a sample with piperidine-DMF (3 7) for 30 min at room temperature. Typically, chitosan substitution levels are 0.08-0.35 mmol/g. 

Fig. 1. Acid cleavable benzyl-type linkers (substitution at CH2).

Olson and coworker showed for ZIF-8, that at 30°C propene adsorbs much faster than propene (Fig. 7). The pore size diameter of ZIF-8 adsorbents could be fine-tuned by Olson using chlorination, bromination, and methylation. Since propene is about 0.2-0.3 A smaller in its critical diameter than propane, the ratio of the diffusivifies of D(propene) D(propane)= 125 [13]. Small changes, big effects. Ref. [13] shows the surprising results that modifying the pore size of the MOF ZIF-8 by linker substitution, the sorption uptake rates of propane and propene can be controlled dramatically. Propene is only slightly (0.2. .. 0.3 A) smaller than propane, but its diffusivity can be 100 times higher. 

Yu D, Kandimalla ER, Cong YP et al (2002) Design, synthesis, and immunostimulatory properties of CpG DNAs containing alkyl-linker substitutions role of nucleosides in the flanking sequences. J Med Chem 45 4540 548... 

The organic and aqueous phases are prepared in separate tanks before transferring to the reaction ketde. In the manufacture of a styrenic copolymer, predeterrnined amounts of styrene (1) and divinylbenzene (2) are mixed together in the organic phase tank. Styrene is the principal constituent, and is usually about 90—95 wt % of the formulation. The other 5—10% is DVB. It is required to link chains of linear polystyrene together as polymerization proceeds. DVB is referred to as a cross-linker. Without it, functionalized polystyrene would be much too soluble to perform as an ion-exchange resin. Ethylene—methacrylate [97-90-5] and to a lesser degree trivinylbenzene [1322-23-2] are occasionally used as substitutes for DVB. 

Pulici and coworkers have reported a solid-phase variation of the Robinson-Gabriel for the production of parallel libraries of ox azole-containing molecules." The preparation is based on a solid supported 2-acylamino ketone 16 that can be cleaved by means of a volatile anhydride and cyclized in solution to obtain a substituted oxazole ring (17) that does not contain traces of the linker moiety. 

This effect is particularly well documented for y - and -amino acid residues [217, 218] which in several natural products (bleomycin A2 [219], calyculins [220]) have been shown to play a substantial role in the pre-organization of the whole molecule into its bioactive conformation. For example, changes in the substitution pattern of the y-amino acid linker in bleomycin A2 result in reduced DNA cleavage efficiency [219]. In the case of y-peptides, changing the relative configuration like or unlike of y " -amino acids has been used as a strategy to generate different local conformations (Fig. 2.34) suitable either for the construction of helices [201] or turns ]202-204]. 

Bifunctional adamantyl, as a hydrophobic central core, can be used to construct peptidic scaffolding [151], as shown in Fig. 27. This is the reason why adamantane is considered one of the best MBBs. This may be considered an effective and practical strategy to substitute different amino acids or DNA segments on the adamantane core (Fig. 28). In other words, one may exploit nucleic acid (DNA or RNA) sequences as linkers and DNA hybridization (DNA probe) to attach to these modules with an adamantane core. Thus a DNA-adamantane-amino acid nanostructure may be produced. 

Chloro- and sulfonamide-substituted aromatic amides showed decreased binding affinity and in vivo potency compared to the simple aliphatic amides. Side chains with an additional (CH2)i-2 linker between the amide and the phenylsulfonamide group resulted in partial or absent in vivo effects [113]. The (CH2)-linked compound, (153), showed around 80-fold selectivity for CB2 over CBi binding [107]. 

In an extension to the xanthenyl theme, the benzyl hydrogen was replaced with a substituted / -methoxyphenyl ring to give linker 35 (Scheme 10) [41]. Peptide amides were cleaved rapidly and in high purity with TFA-DCM (1 9) for 15 min or as a protected fragment with TFA-DCM (1 99) for 3-10 min. 

MAMP (Merrifield, Alpha-MethoxyPhenyl) resin 44 is an alternative to aldehyde linkers to construct TV-substituted amides [53], Nucleophilic displacement of the benzylic chloride with an amine followed by acylation yielded a secondary amide which was released upon a low ( 10%) concentration of TFA (Scheme 16). 

Meisenbach M, Echner H, Voelter W. New methoxy-substituted 9-phenyl-xanthen-9-ylamine linkers for the solid phase phase synthesis of protected peptide amides. Chem Commun (Cambridge) 1997 849-850. 

Fitzpatrick LJ, Rivero RA. Solid phase synthesis of substituted amino-sulfonylureas using a sulfonylcarbamate linker. Tetrahedron Lett 1997 38 7479-7482. 

Wilson LJ, Klopfenstein SR, Li M. A traceless linker approach to the solid phase synthesis of substituted guanidines utilizing a novel acyl isothiocyanate resin. Tetrahedron Lett 1999 40 3999 -002. 

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