Stable Mimetics Research Articles

Semisynthesis of A6-A11 lactam insulin.

Insulin replacement therapy is essential for the management of diabetes. However, despite the relative success of this therapeutic strategy, there is still a need to improve glycaemic control and the overall quality of life of patients. This need has driven research into orally available, glucose-responsive and rapid-acting insulins. A key consideration during analogue development is formulation stability, which can be improved via the replacement of insulin's A6-A11 disulfide bond with stable mimetics. Unfortunately, analogues such as these require extensive chemical synthesis to incorporate the nonnative cross-links, which is not a scalable synthetic approach. To address this issue, we demonstrate proof of principle for the semisynthesis of insulin analogues bearing nonnative A6-A11 cystine isosteres. The key feature of our synthetic strategy involves the use of several biosynthetically derived peptide precursors which can be produced at scale cost-effectively and a small, chemically synthesised A6-A11 macrocyclic lactam fragment. Although the assembled A6-A11 lactam insulin possesses poor biological activity in vitro, our synthetic strategy can be applied to other disulfide mimetics that have been shown to improve thermal stability without significantly affecting activity and structure. Moreover, we envisage that this new semisynthetic approach will underpin a new generation of hyperstable proteomimetics.

Hydrogen Bonding Drives Helical Chirality via 10-Membered Rings in Dipeptide Conjugates of Ferrocene-1,1'-Diamine.

Considering the enormous importance of protein turns as participants in various biological events, such as protein–protein interactions, great efforts have been made to develop their conformationally and proteolytically stable mimetics. Ferrocene-1,1′-diamine was previously shown to nucleate the stable turn structures in peptides prepared by conjugation with Ala (III) and Ala–Pro (VI). Here, we prepared the homochiral conjugates of ferrocene-1,1′-diamine with l-/d-Phe (32/35), l-/d-Val (33/36), and l-/d-Leu (34/37) to investigate (1) whether the organometallic template induces the turn structure upon conjugation with amino acids, and (2) whether the bulky or branched side chains of Phe, Val, and Leu affect hydrogen bonding. Detailed spectroscopic (IR, NMR, CD), X-ray, and DFT studies revealed the presence of two simultaneous 10-membered interstrand hydrogen bonds, i.e., two simultaneous β-turns in goal compounds. A preliminary biological evaluation of d-Leu conjugate 37 showed its modest potential to induce cell cycle arrest in the G0/G1 phase in the HeLa cell line but these results need further investigation.

Cyclic Derivative of Host-Defense Peptide IDR-1018 Improves Proteolytic Stability, Suppresses Inflammation, and Enhances In Vivo Activity.

Host-defense peptides have drawn significant attention as new drugs or drug adjuvants to combat multidrug-resistant bacteria. In this study, we report the development of cyclic derivatives of the immunomodulatory and antibiofilm innate defense regulator peptide (IDR)-1018 based on three different synthetic strategies including head-to-tail cyclization (C1), side-chain-to-tail cyclization (C2), and a disulfide bond cross-linkage (C3). The generated mimetics showed enhanced proteolytic stability and reduced aggregation in vitro and in vivo. The C2 derivative exhibited exceptional ability to suppress inflammation and significantly reduce bacterial loads in a high-density Staphylococcus aureus murine skin infection model. The findings describe different routes to the creation of enzymatically stable mimetics of IDR-1018 and identify a promising new cyclic analogue against bacterial infections.

ChemInform Abstract: Methylidynetrisphosphonates: Promising C1 Building Block for the Design of Phosphate Mimetics

AbstractReview: 53 refs.

Methylidynetrisphosphonates: Promising C1 building block for the design of phosphate mimetics.

Methylidynetrisphosphonates are representatives of geminal polyphosphonates bearing three phosphonate (PO3H2) groups at the bridged carbon atom. Like well-known methylenebisphosphonates (BPs), they are characterized by a P–C–P backbone structure and are chemically stable mimetics of the endogenous metabolites, i.e., inorganic pyrophosphates (PPi). Because of its analogy to PPi and an ability to chelate metal ions, the 1,1,1-trisphosphonate structure is of great potential as a C1 building block for the design of phosphate mimetics. The purpose of this review is to present a concise summary of the state of the art in trisphosphonate chemistry with particular emphasis on the synthesis, structure, reactions, and potential medicinal applications of these compounds.

Synthesis of 1,3- and 2,3-Diglycosylated Indoles as Potential Trisaccharide Mimetics

Diglycosylated heteroaromatics may serve as metabolically stable mimetics of trisaccharides. Herein, the preparation of several 1,3- and 2,3-diglycosylindoles by direct C-glycosylation of monoglycosylated precursors is described.

Sweet (hetero)aromatics: glycosylated templates for the construction of saccharide mimetics

Mono- and diglycosylated aromatics and heteroaromatics may serve as building blocks for the construction of metabolically stable mimetics of oligosaccharides. Methods for their preparation from monosaccharidic precursors by direct C-glycosylation, dipolar cycloaddition or Larock cyclization are described.

Synthesis and conformational behavior of the difluoromethylene linked C-glycoside analog of β-galactopyranosyl-(1↔1)-α-mannopyranoside

C-Glycosides in which the pseudoglycosidic substituent is a methylene group have been advertised as hydrolytically stable mimetics of their parent O-glycosides. While this substitution assures greater stability, the lower polarity and increased conformational flexibility in the intersaccharide linker brought about by this change may compromise biological mimicry. In this regard, C-glycosides, in which the pseudoanomeric methylene is replaced with a difluoromethylene group, are interesting because the CF2 group is more of an isopolar replacement for oxygen than CH2. In addition, the CF2 residue is expected to instill conformational bias into the intersaccharide torsions. Herein is described the synthesis and conformational behavior of the difluoromethylene linked C-glycoside of β-d-galactopyranosyl-(1↔1)-α-d-mannopyranoside. The synthesis centers on the formation of the galactose residue via an oxocarbenium ion–enol ether cyclization. Conformational analysis, using a combination of molecular mechanics, dynamics, and NMR spectroscopy, suggests that the difluoro-C-glycoside populates the non-exo-Gal/exo-Man conformer to a major extent (ca 50%), with a minor contribution (∼15%) from the exo-Gal/exo-Man conformer that corresponds to the ground sate of the parent O-glycoside.

Design, synthesis and bioactions of novel stable mimetics of lipoxins and aspirin-triggered lipoxins

The lipoxins (LX) are a class of potent endogenous oxygenated products that are enzymatically generated from arachidonic acid and have novel anti-inflammatory properties and promote resolution. Elucidation of the biochemical pathways involved in the metabolic inactivation of LX and the discovery of the aspirin-triggered lipoxins (ATL) provided the basis for the design and synthesis of stable analogs of LX and ATL. This special issue review describes the efforts that led to the design and synthesis of stable LX/ATL mimetics, which permitted the detailed elucidation of their novel biological roles, leading to the development of new anti-inflammatory agents that mimic their actions. These synthetic molecules provided the means to uncover the physiologic roles of both the LX and the ATL biosynthetic pathways which led to several unexpected discoveries. Among these findings is the involvement of polyisoprenyl phosphates (PIPP) in intracellular signaling mediated by presqualene diphosphate (PSDP), and the recognition of the novel roles of these lipid mediators in regulating cell trafficking during inflammation as well as in promoting resolution of inflammatory processes. These efforts also provided the basis for examining the potential therapeutic role of LX/ATL stable mimetics and led to the development of new analogs with improved pharmacokinetics that opened the way to potentially new approaches to treating human diseases.

Lipoxin B4 regulates human monocyte/neutrophil adherence and motility: design of stable lipoxin B4 analogs with increased biologic activity.

Lipoxins are biologically active products of arachidonic acid that are formed via cell-cell interactions, particularly those involving leukocytes. Lipoxin A4 and lipoxin B4 (LXB4), within similar concentration ranges, each inhibit human neutrophil, activate monocyte adherence and motility, and are rapidly converted by initial dehydrogenation to other inactive metabolites by human monocytes. Here, we exposed LXB4 to isolated recombinant 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) and found that it was a good substrate for the enzyme (Km=6.9 microM); we identified the major product as 5-oxo-LXB4 via physical methods including liquid chromatography/tandem mass spectrometry. This is the first evidence of 15-PGDH converting a substrate hydroxyl group at a position other than the omega-6 carbon. Based on these observations, several LXB4 analogs were designed and prepared by total organic synthesis to test as stable mimetics: 5(S)-methyl-LXB4-me, 5(R)-methyl-LXB4-me, and 15-epi-LXB4-me (the aspirin-triggered form of LXB4). Both 5(S)-methyl-LXB4-me and 5(R)-methyl-LXB4-me were resistant to rapid conversion. In addition, actions of the stable analogs were evaluated separately with human mono-cytic cells and neutrophils, and 5(S)-methyl-LXB4-me was more potent (nM range) than LXB4 for both cell types. In contrast, 5(R)-methyl-LXB4-me was potent in inhibiting neutrophil transmigration across endothelial monolayers, but did not stimulate monocyte adherence. These results indicate that LXB4 analogs can be designed to resist rapid transformation and retain bioactivity with both monocytes and neutrophils. Moreover, they suggest that LXB4 stable analogs are useful tools to selectively evaluate the modes of actions of LXB4 with different tissues.