Design, Synthesis, and Study of a Novel RXPA380-Proline Hybrid (RXPA380-P) as an Antihypertensive Agent

In drug discovery, molecular modification over the lead molecule is often crucial for the development of a drug. Herein, we report the molecular hybridization design of a novel RXPA380-proline hybrid via linking the parent compound, phosphinic peptide RXPA380, with a proline analogue. The presented synthetic route is straightforward and produces the desired product RXPA380-P in moderate yield. The C- and N-domain constructs of the angiotensin-converting enzyme of RXPA380-P appeared to be poor inhibitors of ACE as compared to the parent compound RXPA380

Role of Matrix Metalloproteinases and Therapeutic Benefits of Their Inhibition in Spinal Cord Injury

This review will focus on matrix metalloproteinases (MMPs) and their inhibitors in the context of spinal cord injury (SCI). MMPs have a specific cellular and temporal pattern of expression in the injured spinal cord. Here we consider their diverse functions in the acutely injured cord and during wound healing. Excessive activity of MMPs, and in particular gelatinase B (MMP-9), in the acutely injured cord contributes to disruption of the blood-spinal cord barrier, and the influx of leukocytes into the injured cord, as well as apoptosis. MMP-9 and MMP-2 regulate inflammation and neuropathic pain after peripheral nerve injury and may contribute to SCI-induced pain. Early pharmacologic inhibition of MMPs or the gelatinases (MMP-2 and MMP-9) results in an improvement in long-term neurological recovery and is associated with reduced glial scarring and neuropathic pain. During wound healing, gelatinase A (MMP-2) plays a critical role in limiting the formation of an inhibitory glial scar, and mice that are genetically deficient in this protease showed impaired recovery. Together, these findings illustrate complex, temporally distinct roles of MMPs in SCIs. As early gelatinase activity is detrimental, there is an emerging interest in developing gelatinase-targeted therapeutics that would be specifically tailored to the acute injured spinal cord. Thus, we focus this review on the development of selective gelatinase inhibitors

Shortcut to Fmoc-protected phosphinic pseudodipeptidic blocks

(Chemical Equation Presented) A three-component condensation reaction of Fmoc-carbamate, aldehydes, and alkylphosphinic acids provides a new, direct, and efficient method for synthesizing Fmoc-protected phosphinic pseudodipeptidic blocks, directly usable for solid-phase peptide synthesis. © 2005 American Chemical Society

Active methylene phosphinic peptides: A new diversification approach

Simple, rapid, and efficient methods for P1′ diversification of phosphinic peptides have been developed, employing alkylation and Knoevenagel-type condensation reactions with active methylene phosphinic scaffolds, thus leading to a wide variety of diversified phosphinic and dehydrophosphinic peptides. © 2006 American Chemical Society

Matrix metalloproteinase 11 (MMP-11; stromelysin-3) and synthetic inhibitors

Matrix metalloproteinase (MMP)-11, or Stromelysin 3, is a particular member of MMP family, a group of zinc-dependent endopeptidases involved in matrix degradation and tissue remodeling. Despite intense efforts since its first characterization 15 years ago, its role and target substrates in different diseases remain largely unknown. While mice with MMP-11 deficiency display no particular phenotype, analysis of different tumorigenesis models with these mice lead to the conclusion that MMP-11 promotes tumor development. In contrast with other MMPs, MMP-11 is unable to degrade any major extracellular matrix component and unlike most of other MMPs that are secreted as inactive proenzymes and activated extracellularly, MMP-11 is secreted under active form. MMP-11 may thus play a unique role in tissue remodeling processes, including those associated with tumor progression. Although MMP-11 and other MMPs have been considered as promising targets to combat cancer, a first series of clinical trials using broad-spectrum MMP inhibitors have not led to significant therapeutic benefits. These disappointing results highlight the need for better understanding of the exact role played by each MMP during the different stages of tumor progression. Among the different strategies to fill this gap, highly specific MMP inhibitors would be of great value. This review provides an update on the selectivity profile of phosphinic MMP-11 synthetic inhibitors developed and discusses the opportunities and limitations to identify inhibitors able to fully discriminate MMP-11 from the other MMPs. © 2006 Wiley Periodicals, Inc

Chemoselective protection of solid-phase compatible Fmoc-phosphinic building blocks

(Chemical Equation Presented) An efficient four-step synthetic strategy able to fully discriminate hydroxyphosphinyl and carboxylic groups of Fmoc-phosphinic building blocks and related analogues has been developed. The proposed method applies selective acidic removal of the phenacyl (Pac) group from the hydroxyphosphinyl functionality and protection by the 1-adamantyl (Ad) group. Reductive removal of the Pac group from the carboxylic functionality leads to Fmoc-protected phosphinic pseudodipeptidic units suitable for phosphinic peptide and library development using solid-phase peptide synthesis (SPPS). © 2006 American Chemical Society

Synthesis of the phosphinic analogue of thyrotropin releasing hormone

(Chemical Equation Presented) The synthesis of the phosphinic analogue of thyrotropin releasing hormone (TRH) GlpΨ[P(O)(OH)]HisProNH2, where the scissile peptide bond of TRH has been replaced by the hydrolytically stable phosphinic bond, has been achieved by a multistep synthetic strategy, providing thus one of the most potent synthetic inhibitors of pyroglutamyl peptidase II (PPII) reported to date (170 nM). The key synthetic step, an Ugi-type condensation reaction, produced directly the suitably protected for solid-phase peptide synthesis pseudodipeptidic block FmocGlu(OMe)Ψ[P(O)(OH)] His(Tr)OH. Formation of the pyroglutamic ring was performed on solid phase, providing thus a general method for synthesizing pyroglutamyl phosphinic peptides on solid phase. Using this strategy, the phosphinic analogue of TRH has been synthesized for the first time. © 2008 American Chemical Society

Unprecedented Convergent Synthesis of Sugar-Functionalization of Phosphinic Acids under Metal-Free Conditions

[Image: see text] A novel TEA-catalyzed sugar-esterification of phosphinic acids was used as a general and efficient approach for the synthesis of a variety of phosphinates without any transition metal. The high efficiency of the current methodology and a convenient experimental procedure compensate for the moderate yields obtained. Another advantage is that the reaction tolerates different substituents attached to the phosphinic acids and the sugar moieties alongside the ease of isolation of the product

A versatile annulation protocol toward novel constrained phosphinic peptidomimetics

(Chemical Equation Presented) The development of a novel 3-center 2-component annulation reaction between α,ω-carbamoylaldehydes and suitably monoalkylated phosphinic acids is reported. Depending on the starting α,ω-carbamoylaldehyde, diverse phosphinic scaffolds varying in the size of their rigidity element, the nature and stereochemistry of substituents, and the participation of heteroatoms in the azacyclic ring system can be obtained in one synthetic step and in high yield. In addition, this methodology allows the synthesis of Fmoc-protected constrained aminophosphinic acids that can be easily converted to suitable pseudodipeptide building blocks compatible with the requirements of peptide synthesis on the solid phase. Finally, the careful choice of both substituents and protecting groups can provide functionally diverse, orthogonally protected constrained scaffolds for extended derivatization of the target phosphinic peptidomimetic structrures. © 2007 American Chemical Society

Novel glycosyl prodrug of RXP03 as MMP-11 prodrug: design, synthesis and virtual screening

Abstract Like most phosphinic acids, the potent and selective RXP03 inhibitor of different MMPs exhibited moderate absorption and low bioavailability, which impaired its use. In an unprecedented attempt, we present an interesting synthetic approach to a new class of phosphinate prodrug, glycosyl ester of RXP03, to provide a potentially improved blood–brain barrier (BBB) behavior compared to the former lead compound RXP03. To validate this speculation, a predictive study for permeability enhancer of glycosyl ester of RXP03 showed encouraging insights to improve drug delivery across biological barriers