12 research outputs found
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
Chiral (salen)Co(III)(N-benzyl-L-serine) derived phosphites : monodentate P-ligands for enantioselective catalytic applications
Reaction of the (S,S)-salen-cobalt(III)-N-benzyl-L-serine complex 2 with four diol-derived chlorophosphites
afforded phosphites 3a–3d in moderate yields (37–72%). Structural studies of these monodentate phosphite ligands and of their Rh-complexes were performed in solution by 1H and 31P NMR spectroscopy.
The ligands were screened in several enantioselective catalytic applications, showing good activity and moderate enantioselectivity in the palladium-catalyzed desymmetrization of meso-cyclopenten-2-ene-1,4-diol biscarbamate
Approaches to the Stereoselective Total Synthesis of (-)-Dictyostatin
The sponge-derived macrolide (-)-dictyostatin (1) has been reported to exhibit paclitaxel-like effects on cellular microtubules and to inhibit human cancer cell proliferation (even of paclitaxel-resistant cancer cell lines) at low nanomolar concentrations, with activity somewhat superior to the already very active discodermolide. Although four total syntheses of (-)-dictyostatin were recently completed, the development of a practical and flexible synthesis remains an important goal, particularly as its natural supply is extremely scarce.
Here we report a highly stereoselective synthesis of the C1\u2013C26 (2), the C10-C26 (3) and the C1\u20139 (4) fragments of (-)-dictyostatin. Work is in progress to complete the total synthesis of (-)-dictyostatin
Approaches to the Stereoselective Total Synthesis of (-)-Dictyostatin
The sponge-derived macrolide (-)-dictyostatin (1) has been reported to exhibit paclitaxel-like effects on cellular microtubules and to inhibit human cancer cell proliferation (even of paclitaxel-resistant cancer cell lines) at low nanomolar concentrations, with activity somewhat superior to the already very active discodermolide. Although four total syntheses of (-)-dictyostatin were recently completed, the development of a practical and flexible synthesis remains an important goal, particularly as its natural supply is extremely scarce.
Here we report a highly stereoselective synthesis of the C1\u2013C26 (2), the C10-C26 (3) and the C1\u20139 (4) fragments of (-)-dictyostatin. Work is in progress to complete the total synthesis of (-)-dictyostatin
A Practical Synthesis of the C1-C9 Fragment of Dictyostatin
A stereoselective synthesis of the C1–C9 fragment of (–)-dictyostatin has been achieved by use of a titanium(IV) chloride
mediated chelation-controlled Mukaiyama aldol reaction and two modified Horner–Wadsworth–Emmons olefinations (Roush–
Masamune and Still–Gennari)
Rhodium-catalyzed asymmetric hydrogenation of olefins with phthalaphos, a new class of chiral supramolecular ligands
A library of 19 binol-derived chiral monophosphites that contain a phthalic acid diamide group (Phthala- Phos) has been designed and synthesized in four steps. These new ligands were screened in the rhodium-catalyzed enantioselective hydrogenation of prochiral dehydroamino esters and enamides. Several members of the library showed excellent enantioselectivity with methyl 2-acetamido acrylate (6 ligands gave >97% ee), methyl (Z)-2- acetamido cinnamate (6 ligands gave >94% ee), and N-(1-phenylvinyl)acetamide (9 ligands gave >95% ee), whilst only a few representatives afforded high enantioselectivities for challenging and industrially relevant substrates N-(3,4-dihydronaphthalen-1- yl)-acetamide (96% ee in one case) and methyl (E)-2-(acetamidomethyl)-3- phenylacrylate (99% ee in one case). In most cases, the new ligands were more active and more stereoselective than their structurally related monodentate phosphites (which are devoid of functional groups that are capable of hydrogen-bonding interactions). Control experiments and kinetic studies were carried out that allowed us to demonstrate that hydrogen-bonding interactions involving the diamide group of the PhthalaPhos ligands strongly contribute to their outstanding catalytic properties. Computational studies carried out on a rhodium precatalyst and on a conceivable intermediate in the hydrogenation catalytic cycle shed some light on the role played by hydrogen bonding, which is likely to act in a substrate-orientation effect
PhthalaPhos: Chiral Supramolecular Ligands for Enantioselective Rhodium-Catalyzed Hydrogenation Reactions
6reservedmixedPignataro, L.; Carboni, S.; Civera, M.; Colombo, R.; Piarulli, Umberto; Gennari, C.Pignataro, L.; Carboni, S.; Civera, M.; Colombo, R.; Piarulli, Umberto; Gennari, C
Supramolecular Catalysts : Investigation of Arene \u3c0-\u3c0 and Acid-Base Interactions to Promote the Assembly of Monodentate P-Ligands
In recent years, monodentate phosphorus ligands have held center stage in asymmetric catalysis, thanks to their outstanding activity, selectivity and convenient, fast and practical synthesis. Bidentate ligands are of course still very important, even though their synthesis is usually more tedious and expensive. Supramolecular bidentate ligands, based on the assembly of monodentate ligands possessing complementary functionalities, combine the essential features of bidentate ligands (preorganization and rigidity) with the advantages of monodentate ligands (practicality). Metal-ligands interactions (Reek, van Leeuwen, Takacs), hydrogen bonds (Breit, Reek, Nishibayashi), and ionic interactions (van Leeuwen) have been so far the main non-covalent forces used to promote the recognition of monodentate ligands.1
Here we report two new approaches for the assembly of monodentate phosphites in Rh-complexes: i) arene \uf070-\uf070 interactions, using a binary combination of an electron-poor (with a perfluroarene or dinitroarene unit) and an electron-rich ligand (with a methoxyarene unit); ii) acid-base interactions, using a binary combination of an acidic (bearing a carboxylic acid) and a basic (bearing a tertiary amine) chiral binaphtholic phosphite.
The preferential formation of the Rh-heterocomplexes was investigated by 31P-NMR and the ligand binary combinations were also tested in the Rh-catalyzed asymmetric hydrogenation of functionalized olefins (methyl acetamidoacrylate and dimethyl itaconate). In both cases, enhanced ee\u2019s (up to 99 %) were obtained using selected heterocobinations with respect to the corresponding homocombinations.
We thank MiUR for a postdoctoral fellowship (to L. Pignataro, PRIN prot. 2006030449), the European Commission [RTN Network (R)Evolutionary Catalysis MRTN-CT-2006-035866] for financial support and for a predoctoral fellowship (to B. Lynikaite) and a postdoctoral fellowship (to J. Cvengro\u161). C. Gennari gratefully acknowledges Merck Research Laboratories for the Merck's Academic Development Program Award