9-fluorenylmethyl esters as carboxyl protecting group

Kessler, Horst; Siegmeier, R.

doi:10.1016/s0040-4039(00)81385-4

Cited by 47 publications

(16 citation statements)

References 2 publications

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“…A comparison of DioRaSSP with the reported methods for repetitive peptide synthesis in solution clearly manifests the following combined benefits of DioRaSSP with respect to the benefits of the individual alternative methods: [20,31,35]. Analytical RP-HPLCs were performed on a Waters HPLC System using a Vydac C18 column (250 × 4.6 mm ID; 5 µm particle size).…”

Section: Comparison Of Diorassp With Other Repetitive Methods In Solumentioning

confidence: 99%

A novel method for repetitive peptide synthesis in solution without isolation of intermediates

Eggen¹,

Bakelaar²,

Petersen³

et al. 2005

J. Peptide Sci.

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A novel method was developed for the large-scale manufacture of peptides in solution, called DioRaSSP-Diosynth Rapid Solution Synthesis of Peptides. This method combines the advantages of the homogeneous character of classical solution-phase synthesis with the universal character and the amenability to automation inherent to the solid-phase approach. The process consists of repetitive cycles of coupling and deprotection in a permanent organic phase and is further characterized by the fact that intermediates are not isolated. Couplings are mediated by water-soluble carbodiimide. Several types of function may be applied for temporary amino protection depending on the sequence of the actual peptide, including Z, Fmoc, Msc and Nsc. Formate is the preferred hydrogen donor during hydrogenolysis of the Z function, while 1,8-diazabicyclo[5.4.0]undec-7-ene is used to deprotect Fmoc, Msc and Nsc. Morpholine is added during the deprotection of Msc and Nsc to scavenge the arising alkenes. Processes according to this highly efficient synthesis method are easy to scale up and yield products of reproducible high purity, which is guaranteed by a new quenching method for residual activated compounds, applying an anion-forming amine such as a beta-alanine ester. This ester should display a lability similar to that of the temporary amino-protecting function, allowing simultaneous deprotection of the growing peptide and the quenched compound. The DioRaSSP approach assures the completely quantitative removal of deprotected quenched compounds before the coupling step of the next cycle of the synthesis by basic aqueous (that is active) extraction, while the growing peptide remains anchored in the organic phase due to the presence of hydrophobic protecting functions.

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Section: Comparison Of Diorassp With Other Repetitive Methods In Solumentioning

confidence: 99%

A novel method for repetitive peptide synthesis in solution without isolation of intermediates

Eggen¹,

Bakelaar²,

Petersen³

et al. 2005

J. Peptide Sci.

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“…Allyl esters can be easily prepared by refluxing the carboxylic acid with allyl bromide in the presence of DIEA,65, 112 or with allyl alcohol in the presence of DCC/dimethylaminopyridine (DMAP) 65. The latter method is also used for the preparation of Fm esters 118, 119. Alternatively, these esters can be obtained from 9‐fluorenylmethylchloroformate in the presence of DIEA/DMAP120 or by transesterification of p ‐nitrophenyl esters in the presence of imidazole 121…”

Section: C‐terminal Carboxyl Protecting Groupsmentioning

confidence: 99%

Orthogonal protecting groups forNα-amino andC-terminal carboxyl functions in solid-phase peptide synthesis

Alberício¹

2000

Biopolymers

107

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For the controlled synthesis of even the simplest dipeptide, the Nα‐amino group of one of the amino acids and the C‐terminal carboxyl group of the other should both be blocked with suitable protecting groups. Formation of the desired amide bond can now occur upon activation of the free carboxyl group. After coupling, peptide synthesis can be continued by removal of either of the two protecting groups and coupling with the free C‐terminus or Nα‐amino group of another protected amino acid. When three functional amino acids are present in the sequence, the side chain of these residues also has to be protected. It is important that there is a high degree of compatibility between the different types of protecting groups such that one type may be removed selectively in the presence of the others. At the end of the synthesis, the protecting groups must be removed to give the desired peptide. Thus, it is clear that the protection scheme adopted is of the utmost importance and makes the difference between success and failure in a given synthesis. Since R. B. Merrifield introduced the solid‐phase strategy for the synthesis of peptides, this prerequisite has been readily accepted. This strategy is usually carried out using two main protection schemes: the tert‐butoxycarbonyl/benzyl and the 9‐flourenylmethoxycarbonyl/tert‐butyl methods. However, for the solid‐phase preparation of complex or fragile peptides, as well as for the construction of libraries of peptides or small molecules using a combinatorial approach, a range of other protecting groups is also needed. This review summarizes other protecting groups for both the Nα‐amino and C‐terminal carboxyl functions. © 2000 John Wiley & Sons, Inc. Biopoly 55: 123–139, 2000

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“…For the synthesis of acids 2i,j bearing an additional ester group, a suitable carboxyl protecting group had to be incorporated at an appropriate stage to allow the Wittig condensation and to ensure the removal of the terminal carboxyl group while preserving the intrachain ester linkage. We anticipated being able to fulfill this task using the 9‐fluorenylmethyl ester group 56. Thus, Wittig condensation of the phosphonium salt 13 , which was prepared in a similar way as its tert ‐butyl ester counterpart 8e , with 3‐tetrahydropyranyloxy‐propionaldehyde ( 14 )57 gave ester 15a in 22% yield.…”

Section: Chemistrymentioning

confidence: 99%

Improving the Antitumor Activity of Squalenoyl‐Paclitaxel Conjugate Nanoassemblies by Manipulating the Linker between Paclitaxel and Squalene

Caron¹,

Maksimenko²,

Wack³

et al. 2012

Adv Healthcare Materials

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A series of new lipid prodrugs of paclitaxel, which can be formulated as nanoassemblies, are described. These prodrugs which are designed to overcome the limitations due to the systemic toxicity and low water solubility of paclitaxel consist of a squalene chain bound to the 2'-OH of paclitaxel through a 1,4-cis,cis-dienic linker. This design allows the squalene-conjugates to self-assemble as nanoparticular systems while preserving an efficient release of the free drug, thanks to the dienic spacer. The size, steric hindrance, and functional groups of the spacer have been modulated. All these prodrugs self-assemble into nanosized aggregates in aqueous solution as characterized by dynamic light scattering and transmission electron microscopy and appear stable in water for several days as determined by particle size measurement. In vitro biological assessment shows that these squalenoyl-paclitaxel nanoparticles display notable cytotoxicity on several tumor cell lines including A549 lung cell line, colon cell line HT-29, or KB 3.1 nasopharyngeal epidermoid cell line. The cis,cis-squalenyl-deca-5,8-dienoate prodrug show improved activity over simple 2'-squalenoyl-paclitaxel prodrug highlighting the favourable effect of the dienic linker. The antitumor efficacy of the nanoassemblies constructed with the more active prodrugs has been investigated on human lung (A549) carcinoma xenograft model in mice. The prodrug bearing the cis,cis-deca-5,8-dienoyl linker shows comparable antitumor efficacy to the parent drug, but reveals a much lower subacute toxicity as seen in body weight loss. Thus, nanoparticles with the incorporated squalenoyl paclitaxel prodrug may prove useful for replacement of the toxic Cremophor EL.

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9-fluorenylmethyl esters as carboxyl protecting group

Cited by 47 publications

References 2 publications

A novel method for repetitive peptide synthesis in solution without isolation of intermediates

A novel method for repetitive peptide synthesis in solution without isolation of intermediates

Orthogonal protecting groups forNα-amino andC-terminal carboxyl functions in solid-phase peptide synthesis

Improving the Antitumor Activity of Squalenoyl‐Paclitaxel Conjugate Nanoassemblies by Manipulating the Linker between Paclitaxel and Squalene

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