Macrocyle-embedded b-lactams as novel inhibitors of the Penicillin Binding Protein PBP2a from MRSA

in European Journal of Medicinal Chemistry (2013), 64

Synthesis of poly(lactide-co-glycolide-co-ε-caprolactone)-graft-mannosylated poly(ethylene oxide) copolymers by combination of “clip” and “click” chemistries

in Biomacromolecules (2012), 13(3), 760-768

Poly(lactide-co-glycolide) (PLGA) is extensively used in pharmaceutical applications, for example, in targeted drug delivery, because of biocompatibility and degradation rate, which is easily tuned by the ... [more ▼]

Poly(lactide-co-glycolide) (PLGA) is extensively used in pharmaceutical applications, for example, in targeted drug delivery, because of biocompatibility and degradation rate, which is easily tuned by the copolymer composition. Nevertheless, synthesis of sugar-labeled amphiphilic copolymers with a PLGA backbone is quite a challenge because of high sensitivity to hydrolytic degradation. This Article reports on the synthesis of a new amphiphilic copolymer of PLGA grafted by mannosylated poly(ethylene oxide) (PEO). A novel building block, that is, α-methoxy-ω-alkyne PEO-clip-N-hydroxysuccinimide (NHS) ester, was prepared on purpose by photoreaction of a diazirine containing molecular clip. This PEO block was mannosylated by reaction of the NHS ester groups with an aminated sugar, that is, 2-aminoethyl-α-d-mannopyroside. Then, the alkyne ω-end-group of PEO was involved in a copper alkyne- azide coupling (CuAAC) with the pendent azides of the aliphatic copolyester. The targeted mannose-labeled poly(lactide-co-glycolide-co-ε-caprolactone)-graft-poly(ethylene oxide) copolymer was accordingly formed. Copolymerization of d,l-lactide and glycolide with α-chloro-ε-caprolactone, followed by substitution of chlorides by azides provided the azido-functional PLGA backbone. Finally, micelles of the amphiphilic mannosylated graft copolymer were prepared in water, and their interaction with Concanavalin A (ConA), a glyco-receptor protein, was studied by quartz crystal microbalance. This study concluded to the prospect of using this novel bioconjugate in targeted drug delivery. [less ▲]

Unprecedented inhibition of resistant penicillin binding proteins by bis-2-oxoazetidinyl macrocycles

in MedChemComm (2012), 3

"Clip" and "click" chemistries combination: toward easy PEGylation of degradable aliphatic polyesters

in Macromolecular Rapid Communications (2011), 32(7), 616-621

The combination of “clip” and “click” reactions provides a versatile and straightforward pathway for the synthesis of functional amphiphilic and degradable copolymers valuable for biomedical applications ... [more ▼]

The combination of “clip” and “click” reactions provides a versatile and straightforward pathway for the synthesis of functional amphiphilic and degradable copolymers valuable for biomedical applications such as targeted drug-delivery vehicles. [less ▲]

(Di)-aminoguanidine Functionalization through Transamination: An Avenue to an Auspicious Class of Supramolecular Synthons

in Crystal Growth & Design (2011), 11

Cyclodimerization by ring-closing metathesis: synthesis, computational and biological evaluation of novel bis-azetidinyl-macrocycles

in Tetrahedron (2010), 66

Targeting of tumor endothelium by RGD-grafted PLGA-nanoparticles loaded with Paclitaxel

in Journal of Controlled Release (2009), 140(2), 166-173

Paclitaxel (PTX)-loaded PEGylated PLGA-based nanoparticles (NP) have been previously described as more effective in vitro and in vivo than Taxol®. The aim of this study was to test the hypothesis that our ... [more ▼]

Paclitaxel (PTX)-loaded PEGylated PLGA-based nanoparticles (NP) have been previously described as more effective in vitro and in vivo than Taxol®. The aim of this study was to test the hypothesis that our PEGylated PLGA-based nanoparticles grafted with the RGD peptide or RGD-peptidomimetic (RGDp) would target the tumor endothelium and would further enhance the anti-tumor efficacy of PTX. The ligands were grafted on the PEG chain of PCL-b-PEG included in the nanoparticles. We observed in vitro that RGD-grafted nanoparticles were more associated to Human Umbilical Vein Endothelial cells (HUVEC) by binding to αvβ3 integrin than non-targeted nanoparticles. Doxorubicin was also used to confirm the findings observed for PTX. In vivo, we demonstrated the targeting of RGD and RGDp-grafted nanoparticles to tumor vessels as well as the effective retardation of TLT tumor growth and prolonged survival times of mice treated by PTX-loaded RGD-nanoparticles when compared to non-targeted nanoparticles. Hence, the targeting of anti-cancer drug to tumor endothelium by RGD-labeled NP is a promising approach. [less ▲]

Light induced functionalization of PCL-PEG block copolymers for the covalent immobilization of biomolecules

in Biomacromolecules (2009), 10(4), 966-974

Functionalized poly-ε-caprolactone-block-polyethyleneglycol (PCL-PEG) amphiphilic copolymers were prepared to be constituents of nanocarriers used for the targeting of specific cells. Hence, we conceived ... [more ▼]

Functionalized poly-ε-caprolactone-block-polyethyleneglycol (PCL-PEG) amphiphilic copolymers were prepared to be constituents of nanocarriers used for the targeting of specific cells. Hence, we conceived a smooth and simple photografting methodology on these copolymers using a bifunctional molecular clip (O-succinimidyl-4-(p-azido-phenyl)butanoate). We prepared PCL-PEGs with pendent N-hydroxysuccinimide esters and studied the grafting with 3H-lysine, which radioactivity was counted by LSC. Several parameters were investigated, such as behavior of homopolymers, initial concentrations, irradiation, and incubation durations. Evidences of a “PEG directed photografting” are discussed and this selectivity could be improved by a selective solvent technique. The photografting on different PCL-PEGs revealed a dependency of the rates to the crystallinity of the copolymers. Several controls by SEC, DLS, and TEM of the treated copolymers were realized. Lastly, the coupling of α-d-mannopyranoside ligand was performed, reaching amounts of 5400 nmol/g of PCL-PEG. This derivatized PCL-PEG enters in the preparation of nanocarriers used for the targeting of antigen presenting cells. [less ▲]

Aminophosphonic Acids and Aminobis(phosphonic acids) as Potential Inhibitors of Penicillin-Binding Proteins

in European Journal of Organic Chemistry (2009), (1), 85-97

Abstract Aminophosphonic acids and aminobis(phosphonic acids) have been prepared by the alkylation of Schiff bases with methyl bromoacetate or ethyl acrylate. Other pathways, like the modified Pudovik ... [more ▼]

Abstract Aminophosphonic acids and aminobis(phosphonic acids) have been prepared by the alkylation of Schiff bases with methyl bromoacetate or ethyl acrylate. Other pathways, like the modified Pudovik reaction and Kabachnik-Fields reaction, have been considered for the synthesis of the -phosphonic bioisoster of aminocitrate. Partial or complete deprotection of the phosphonate ester have been realised by either acidic hydrolysis or by treatment with trimethylsilyl bromide. Evaluation against penicillin-binding proteins has shown that our compounds are modest inhibitors of class A -lactamases, but have an interesting activity against R39 (D,D-peptidase/carboxypeptidase). [less ▲]

Large ring 1,3-bridged 2-azetidinones: experimental and theoretical studies

in European Journal of Medicinal Chemistry (2009), 44