Combinatorial chemistry, combined with recent advances in robotic screening, which enable the testing of a large number of compounds in a short period of time, is becoming an important tool in accelerating drug discovery. This technique involves the preparation of a large number of structurally related compounds either as mixtures in the same reaction vessel or individually by parallel synthesis. In this manner large pools of similar compounds can be synthesized within a short period of time. Combinatorial libraries have been prepared using both solution chemistry and by solid phase synthesis; however, solid phase synthesis allows the use of excess reagents to drive the reaction to completion and easy removal of the reagents and side-products by simple filtration of the polymeric support and washing with solvent. Therefore, solid phase synthesis offers a more attractive approach to the generation of chemical libraries for screening purposes.
One of the key elements in solid phase chemistry is the polymeric resin. Since the introduction of the Merrifield resin, libraries of peptides, nucleotides, and organic molecules have been generated on solid supports. Many of the resins that are currently employed as supports were originally developed for the synthesis of peptides. Polar functionalities such as carboxylic acids and amides were released upon cleavage of products from the resins. Recent advances in linker technology have allowed other polar functional groups, such as alcohols and thiols, also to be attached to the polymer support. In fact, most of the linkers available for solid support synthesis to date require polar functional groups for binding, and the same polar groups are released after cleavage. To generate libraries with biological activity, however, such polar functionalities may possess unfavorable pharmacological properties. Because of poor oral bioavailability and enzymatic degradation of linear peptides, modified peptides, peptidomimetics, and cyclic peptides have become appealing targets for the design of therapeutic agents with increased pharmacological activities. Therefore, we directed our attention to the design of new solid support linkers for non-polar or aromatic compounds that are commonly found in medicinally important agents.
Solid-phase peptide synthesis ..
strategy in three consecutive reaction sequences, a protected linear intermediate 41 was produced. Deprotection of the ester and amine functionalities gave a polymer-bound depsipeptide, which was cyclized with HBTU and DIPEA in NMP. Sansalvamide (33) was obtained by TFA cleavage from the solid support in a 67% overall yield for the 12 solid-phase steps, based on the initial loading level of 38. A comparison of the 1H NMR spectra of synthetic sansalvamide and a sample of the natural product (donated by Professor William Fenical, Scripps Institution of Oceanography) indicated that the synthetic material was identical to that of the natural product with >95% purity.
Background Solid phase synthesis is a process by which ..
The arylsilyl linkage was found to be resistant to moderate acidic [1 HCl/THF (1:8); 50% TFA/ CH2Cl2 for 10 min] and basic conditions [LiOH, THF/H2O (8:1), heat] as well as to the general amide coupling reactions. Both -Boc and -Fmoc-protection strategies employed for the preparation of dipeptides 9 indicate that this versatility may be of great value for the solid-phase synthesis of complex molecules requiring various orthogonal protection of amine intermediates.
Solid Phase Synthesis of a Functionalized Bis-Peptide …
The synthetic approach presented herein provides a method for the synthesis of functionalized bis-peptides from bis-amino acid building blocks using common solid-phase peptide synthesis techniques. The monomer synthesis of these "Pro4" building blocks from trans-4-hydroxyproline3 is highly scalable and has been successfully completed to the hydantoin stage at a 600 mmol (234 g) scale (unpublished). Once the monomers are in hand, the use of solid-phase techniques provides a more rapid method of bis-peptide synthesis than our current solution-phase methodology4 by eliminating the need for reaction work-ups and intermediate purifications.
Improving the Fmoc Solid Phase Synthesis of ..
Head-to-tail cyclization of peptides on the resin provides a facile route to cyclic compounds. In addition to general advantages of solid phase synthesis, such as high efficiency and easy purification, head-to-tail cyclization of peptides on polymer supports provides minimal risk of intermolecular reactions (e.g., dimerization and oligomerization), even under high concentration. This is another advantage over solution chemistry which requires high dilution conditions to avoid intermolecular side reactions of the linear peptide. The synthesis of cyclic peptides via a traceless aromatic side-chain attachment with head-to-tail cyclization on the solid support also will be discussed.
US9388212B2 - Solid phase peptide synthesis via side …
The primary challenge in solid-phase synthesis is diagnosing synthetic progress and problem solving since no intermediates are isolated. This has lead to the development of many colorimetric tests including those to identify if free amines (Kaiser Test10) or free hydroxyls (Methyl Red Test7) are exposed on resin. Unfortunately, the commonly used Kaiser Test10 is not generally applicable in our solid-phase synthesis due to the almost exclusive use of secondary amines or amines attached to a quaternary carbon. Other options for assessment on HMBA resin include test cleavages using a nucleophile such as hydrazine11, quantitative Fmoc cleavage monitored by UV/Vis1,11, and trapping and analyzing incoming activated compounds.