Tumor targeting via integrin ligands: synthesis and biological evaluation of RGD peptidomimetic-paclitaxel conjugates

Integrins are a large family of heterodimeric transmembrane glycoprotein receptors, composed by two non-covalently-associated subunits (\u3b1 and \u3b2). Integrins \u3b1V\u3b23 and \u3b1V\u3b25 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 \u3b1V\u3b23 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 \u3b1V\u3b23 at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (\u3b1V\u3b23 12) and its subclone CCRF-CEM \u3b1V\u3b23 (\u3b1V\u3b23 +). A fairly effective integrin-targeting was displayed by conjugate 3, which was found to inhibit cell proliferation with increased selectivity towards \u3b1V\u3b23-expressing cells compared to the free PTX

Multivalency Increases the Binding Strength of RGD Peptidomimetic-Paclitaxel Conjugates to Integrin αVβ3

Herein we report the synthesis of three multimeric RGD peptidomimetic-paclitaxel conjugates featuring a number of \u3b1V\u3b23 integrin ligands ranging from 2 to 4 (compounds 7-9). These constructs were assembled by conjugation of the integrin \u3b1V\u3b23 ligand cyclo[DKP-RGD]-CH2NH2 (2) with paclitaxel (3) via a 2\u2019-carbamate with a self-immolative spacer, the lysosomally cleavable Val-Ala dipeptide linker, a multimeric scaffold, a triazole linkage, and finally a PEG spacer. Two monomeric conjugates (compounds 5-6) were also synthesized as reference compounds. Remarkably, the new multimeric conjugates showed a binding affinity for the purified integrin \u3b1V\u3b23 receptor which increased with the number of integrin ligands (reaching a minimum IC50 value of 1.2 nM for the trimeric), thus demonstrating that multivalency is an effective strategy to strengthen the ligand-target interactions

Human toxocariasis: contribution by Brazilian researchers

In the present paper the main aspects of the natural history of human infection by Toxocara larvae that occasionally result in the occurrence of visceral and/or ocular larva migrans syndrome were reviewed. The contribution by Brazilian researchers was emphasized, especially the staff of the Tropical Medicine Institute of São Paulo (IMT)

Cyclic RGD-peptidomimetics containing bifunctional diketopiperazine scaffolds as new potent integrin ligands

Integrins 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

Rationally designed chiral enol borinates: Powerful reagents for the stereoselective synthesis of natural products

We 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

Che fine ha fatto la Gazzetta Chimica Italiana?

La \u201cGazzetta Chimica Italiana\u201d cess\uf2 la pubblicazione nel dicembre 1997 quando, fondendosi con altri storici giornali europei, dette origine all\u2019European Journal of Inorganic Chemistry (EurJIC) ed all\u2019European Journal of Organic Chemistry (EurJOC), di cui la SCI \ue8 attualmente comproprietaria. Oggi, a distanza di poco pi\uf9 di dieci anni, questo articolo cerca di fare il punto sull\u2019eredit\ue0 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

Boron 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