Saïd El Kazzouli

Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems: A concise overview

Drugs are introduced into the body by numerous routes such as enteral (oral, sublingual and rectum administration), parenteral (intravascular, intramuscular, subcutaneous and inhalation administration), or topical (skin and mucosal membranes). Each route has specific purposes, advantages and disadvantages. Today, the oral route remains the preferred one for different reasons such as ease and compliance by patients. Several nanoformulated drugs have been already approved by the FDA, such as Abelcet®, Doxil®, Abraxane® or Vivagel®(Starpharma) which is an anionic G4-poly(L-lysine)-type dendrimer showing potent topical vaginal microbicide activity. Numerous biochemical studies, as well as biological and pharmacological applications of both dendrimer based products (dendrimers as therapeutic compounds per se, like Vivagel®) and dendrimers as drug carriers (covalent conjugation or noncovalent encapsulation of drugs) were described. It is widely known that due to their outstanding physical and chemical properties, dendrimers afforded improvement of corresponding carried-drugs as dendrimer-drug complexes or conjugates (versus plain drug) such as biodistribution and pharmacokinetic behaviors. The purpose of this manuscript is to review the recent progresses of dendrimers as nanoscale drug delivery systems for the delivery of drugs using enteral, parenteral and topical routes. In particular, we focus our attention on the emerging and promising routes such as oral, transdermal, ocular and transmucosal routes using dendrimers as delivery systems.

Dendrimer Space Exploration: An Assessment of Dendrimers/Dendritic Scaffolding as Inhibitors of Protein–Protein Interactions, a Potential New Area of Pharmaceutical Development

Dendritic Scaffolding as Inhibitors of Protein−Protein Interactions, a Potential New Area of Pharmaceutical Development Serge Mignani,*,† Saïd El Kazzouli,‡ Mosto M. Bousmina,‡,§ and Jean-Pierre Majoral* †Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, Universite ́ Paris Descartes, Sorbonne Paris Cite,́ 45 rue des Saints Per̀es, 75006 Paris, France ‡Euro-Mediterranean University of Fez, Fes̀-Shore, Route de Sidi harazem, Fes̀, Morocco Hassan II Academy of Science and Technology, Avenue Mohammed VI, 10222 Rabat, Morocco Laboratoire de Chimie de Coordination, Centre National de la Recherche Scientifique, 205 route de Narbonne, 31077 Toulouse Cedex 4, France

Design and synthesis of 2-phenylimidazo[1,2-a]pyridines as a novel class of melatonin receptor ligands.

A novel class of imidazo[1,2-a]pyridines as melatonin receptor ligands is designed and synthesized. The affinities of 3-(6-methoxy-2-phenylimidazo[1,2-a]pyridine-3-yl)-N-methyl-propionamide 8, N-[2-(6-methoxy-2-phenylimidazo[1,2-a]pyridine-3-yl)-ethyl]-acetamide 13 and N-(1-hydroxy-3-(5-methoxy-2-phenyl-1H-indol-3-yl)propan-2-yl)acetamide 18 are evaluated for binding on melatonin receptors. Compound 8 present good selectivity for MT(2) over MT(1) (MT(1)/MT(2) = 19) and compound 13 have good affinities for both MT(1) (Ki :28 nM) and MT(2) (Ki : 8 nM).

Influence of polar support for the synthesis of large C-terminal peptide aldehyde: application to chemoselective ligation

Abstract Efficient conditions have been developed for the synthesis of large peptide aldehydes from solid support through nucleophilic displacement. Aminolysis of the ester bond between a deprotected peptide and the phenylacetamidomethyl linker with aminoacetaldehyde-dimethylacetal leads to a peptide aldehyde masked as an acetal. Besides the optimization of parameters such as solvents, workup procedure and temperature, the influence of the nature of the polymeric support was crucial. Among the solid supports tested, the poly(ethylene glycol)-poly(acrylamide) resin proved to afford the best cleavage yield. This work underlines that the solid support has to be considered as a co-solvent rather than an inert carrier. Our methodology was further applied to the synthesis of a 33-mer with T-helper activity from the fusion protein of measles virus. The 33-mer peptide aldehyde was then chemoselectively ligated via an oxime bond to an (aminooxy) acetyl peptide with T-cytotoxic activity.

Supported synthesis and functionnalization of 2''-deoxyuridine by Suzuki-Miyaura cross-coupling.

The synthesis and modification of 2′-deoxyuridine has been realized under Suzuki-Miyaura palladium-catalyzed cross-coupling conditions. Using Pd(PPh 3 ) 4 and Na 2 CO 3 , 5-iodo-2′-deoxyuridine bound to solid support is coupled with various boronic acids to give 5-(hetero)aryl-2′-deoxyuridine. Pd(PPh 3 ) 4 palladium catalyzed was found to be superior to Pd(OAc) 2 and (NHC)Pd(allyl)Cl for Suzuki-Miyaura palladium-catalyzed reactions.

Original Multivalent Gold(III) and Dual Gold(III)–Copper(II) Conjugated Phosphorus Dendrimers as Potent Antitumoral and Antimicrobial Agents

Original metallophosphorus dendrimers (generation 3, 48 terminal groups) have been prepared via the complexation of phosphorus dendrimers bearing imino-pyridino end groups with Au(III) or with both Au(III) and Cu(II). The complexation of the dendrimer with Au(III), leading to 1G3-[Au48][AuCl4]48, strongly increased the antiproliferative activities against both KB and HL-60 tumoral cell lines, showing IC50s in the low nanomolar range. It can be noticed also that this gold conjugated phosphorus dendrimer displayed low activity on the quiescent cell line EPC versus its potent antiproliferative activity against actively dividing cells. In order to evaluate the potential synergistic effect between Au(III) and Cu(II) and the influence of the number of Au(III) moieties on the surface of dendrimer against the proliferative activities, nine other original dendrimers with several surface modifications have been prepared. Whatever the number of Au(III) moieties introduced on the surface of dendrimers, all the dendrimers prepared displayed similar potency (nanomolar range) to 1G3-[Au48][AuCl4]48 against KB and HL60. In marked contrast synergistic effects on the antimicrobial activity of some of these phosphorus dendrimers are observed when both Au(III) and Cu(II) are present on the dendritic structure.

Palladium-Catalyzed C3 Arylations of 1H and 2H Pyrazolo[4,3-b]pyridines on Water

Direct C3-arylation of 1 H-pyrazolo[4,3- b]pyridines and direct C3-arylation of 2 H-pyrazolo[4,3- b]pyridines in water has been developed. A new protocol for a sequential C3-arylation procedure on a mixture of 1 H- and 2 H-pyrazolo[4,3- b]pyridines followed by in situ PMB cleavage has also been achieved. This procedure led to unprotected ( NH) C3-arylated 1 H-pyrazolo[4,3- b]pyridines in good yields.