1,721,108 research outputs found
Tumor targeting via integrin ligands: synthesis and biological evaluation of RGD peptidomimetic-paclitaxel conjugates
Full text linkIntegrins are a large family of heterodimeric transmembrane glycoprotein receptors, composed by two non-covalently-associated subunits (α and β). Integrins αVβ3 and αVβ5 have been found to be overexpressed on blood vessels in human tumors, but not on vessels in normal human tissues. For this reason, these integrins have become attractive targets for pharmacological studies mainly in the oncology area. The Gennari and Piarulli group recently developed a peptidomimetic compound (1) containing the RGD (Arg-Gly-Asp) sequence and a diketopiperazine (DKP) scaffold as powerful αVβ3 integrin ligand.[1] A functionalized analogue of this ligand (2)[2] was linked to Paclitaxel through two lysosomally cleavable linkers (namely the Val-Ala and Phe-Lys peptide sequences).[3]
The resulting compounds 3 and 4 were subjected to stability assays in the presence of cathepsin B and lysosome extract, revealing that the free Paclitaxel is efficiently released under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing αVβ3 at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (αVβ3 −) and its subclone CCRF-CEM αVβ3 (αVβ3 +). A fairly effective integrin-targeting was displayed by conjugate 3, which was found to inhibit cell proliferation with increased selectivity towards αVβ3-expressing cells compared to the free PTX
Design and synthesis of potent integrin ligands containing a bifunctional diketopiperazine scaffold : stereochemical properties, conformational preferences and biological activities
No full textRationally designed chiral enol borinates: Powerful reagents for the stereoselective synthesis of natural products
No full textWe recently described the development of a quantitative transition state model for the prediction of stereoselectivity in the boron-mediated aldol reaction. This model provides qualitative insights into the factors contributing to the stereochemical outcome of a variety of reactions of synthetic importance. The force field model was used to assist the design and preparation of new chiral boron ligands derived from menthone. The chiral boron enolates were used in various stereoselective processes, including the addition to chiral aldehydes and the reagent-controlled total synthesis of (3S,4S)-statine. The chiral enolates derived from alpha-halo and alpha-oxysubstituted thioacetates were added to aldehydes and imines. Addition to imines leads to the enantioselective synthesis of chiral aziridines, a formal total synthesis of (+)thiamphenicol, and a new highly efficient synthesis of the paclitaxel (taxol(R)) C-13 side-chain and taxol semisynthesis from baccatin III. The stereochemical outcome of the addition to imines was rationalised with the aid of computational studies
Design and synthesis of potent integrin ligands containing a bifunctional diketopiperazine scaffold : approaches to tumor targeted cytotoxic drug delivery
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Cyclic RGD-peptidomimetics containing bifunctional diketopiperazine scaffolds as new potent integrin ligands
No full textIntegrins are glycoprotein heterodimers that control diverse cell functions such as growth, differentiation, proliferation and migration, therefore contributing to important physiological processes, for instance hemostasis and angiogenesis. A great amount of work has been devoted to the study and use of short peptide sequences of the endogenous ligands, that are known to be essential regulators of integrin activation or inactivation. In particular, the RGD sequence, a common motif of several endogenous integrin ligands, has been widely utilized for the construction of biologically active peptides and peptidomimetics. Conformationally rigid spacers have also been used to induce the correct spatial presentation of the RGD pharmacophoric groups. In this subject field, we envisioned the synthesis, conformational analysis and investigation of the biological activity of cyclic RGD-peptidomimetics, containing our recently reported bifunctional diketopiperazine scaffold DKP-1 or its trans-analogue DKP-2. The RGD peptidomimetics 3 and 4 were prepared in moderate to good yields by solution phase peptide synthesis using a Boc protection strategy and t-Bu/Mtr side chain protection. Conformational studies were performed in solution by 1H-NMR spectroscopy and computational methods (restrained molecular dynamics and docking studies), revealing that derivative 4 is better pre-organized for the interaction with the alphavbeta3 integrin receptor. The cyclic RGD peptides were then examined in vitro for their abilities to compete with biotinylated vitronectin for binding to the purified alphavbeta3 receptor, obtaining an excellent value of IC50 = 3.2 nM for derivative 4. Further studies aimed at the synthesis of modified cyclic RGD-peptidomimetics and screening with different biological targets are currently underway
Che fine ha fatto la Gazzetta Chimica Italiana?
No full textLa “Gazzetta Chimica Italiana” cessò la pubblicazione nel dicembre 1997 quando, fondendosi con altri storici giornali europei, dette origine all’European Journal of Inorganic Chemistry (EurJIC) ed all’European Journal of Organic Chemistry (EurJOC), di cui la SCI è attualmente comproprietaria. Oggi, a distanza di poco più di dieci anni, questo articolo cerca di fare il punto sull’eredità scientifica e storica della rivista fondata nel 1871 da Cannizzaro e da altri grandi chimici italiani mettendo in luce i molti aspetti positivi e quelli ancora da migliorare di questa operazione
Boron aldol reaction of alpha-halosubstituted thioacetates with silyl imines: A highly enantio- and diastereoselective synthesis of aziridines
No full textBoron enolates derived from tert-butyl alpha-halothioacetate and bearing menthone-derived chiral ligands react with imines with excellent diastero- and enantiocontrol to give syn alpha-halo-beta-aminothioesters, which can be converted to the corresponding aziridines by simple ring closure during LAH reduction. A key precursor of antibiotics (+)-thiamphenicol and (-)-florfenicol was synthesized. Copyright (C) 1996 Elsevier Scienc
CHELATION-CONTROLLED ENANTIOSELECTIVE SYNTHESIS OF KEY INTERMEDIATES FOR THE PREPARATION OF CARBAPENEM ANTIBIOTICS PS-5 AND 1-BETA-METHYL-PS-5
No full textReaction of the E silyl ketene acetal derived from (1S,2R)-N-methylephedrine butyrate (7) with TiCl4 and β-alkoxy aldehyde 5 gave the aldol product in 75% yield as a 78:11:11 mixture of stereoisomers. In agreement with a chelated transition structure model, the major isomer is syn (2R,3S). The condensation product was transformed into 3, a key intermediate for the preparation of (+)-PS-5 [8:1 trans-cis; ee(trans) = 75%]. The stereoselectivity of the aldol reaction was substantially improved by using α-methyl-β-alkoxy aldehyde 6, which was synthesized in 91% enantiomeric excess and 50% overall yield starting from (1S,2R)-N-methylephedrine propionate E silyl ketene acetal 13. In this case the reaction of silyl ketene acetal 7 with TiCl4 and aldehyde 6 gave the aldol product in 70% yield as a single isomer out of the eight possible isomers. The result is in agreement with a chelated transition structure model and with a kinetic resolution-matched pair mechanism. The condensation product was transformed into 4 and 18, key intermediates for the preparation of 1β-methyl-PS-5 (ee > 99%). Via a different approach, the reaction of enantiomerically pure aldehyde (S)-(+)-6, prepared from (R)-(-)-methyl 3-hydroxy-2-methylpropionate, with TiCl4 and achiral E or Z silyl ketene acetals 19 or 20 gave the aldol product in high yield respectively as a 99:1:0:0 or 96:3:1:0 mixture of stereoisomers. The major isomer 21, obtained in agreement with a chelated transition structure model, was transformed into the key intermediate 18 via the same reaction sequence
Biosynthesis of mycophenolic acid. Oxidation of 6-farnesyl-5,7-dihydroxy-4- methylphthalide in a cell-free preparation from Penicillium brevicompactum
No full textThe conversion of 6-farnesyl-5,7-dihydroxy-4-methylphthalide (5) into mycophenolic acid (1) proceeds through the hydroxy-ketone (11) by oxidation of the central double bond
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