1,721,073 research outputs found
Asymmetric reduction by transition metals complexes and biocatalysts
No full textIn the last years the importance of α- and -amnimoacids is increased since these molecules are interesting synthons for the preparation of unnatural peptides and bioactive compounds, in particular antibiotics or anticancer.
They can be easily obtained in optically pure form by reduction using metal catalyzed asymmetric hydrogenation1(chemocatalysis) or by enzyme mediated reduction2 (biocatalysis). In particular with the biocatalytical approach we used whole cells of different microorganisms endowed with enantioselective dehydrogenases, in chemocatalysis we used essentially Ir(I) and Ru(II) complexes of different atropoisomeric diphosphines.
In both cases our research efforts let us to obtain chiral enriched unnatural aminoacids by reduction of prochiral ketones3 and by reduction of tetra substituted double bonds4, which are generally very low active. Our research will show that the process robustness and stereochemical outcome is strongly dependent on thermodynamic parameters but also on the presence of additives.
We will discuss in detail nature and function of such compounds and we will demonstrate that it is possible to combine metal enantioselective reduction with stereoselective biocatalytic one.
1. E. Cesarotti; I. Rimoldi, P. Spalluto, F. Demartin Tetrahedron Asymmetry. 2007, 18, 1278-1283.
2. R. Gandolfi, E. Cesarotti, F. Molinari; D. Romano; I. Rimoldi Tetrahedron Asymmetry. 2009, 20, 411-414.
3. I. Rimoldi, E. Cesarotti, D. Zerla, F. Molinari, D. Albanese, R. Gandolfi submitted
4. R. Gandolfi, E. Cesarotti, D. Zerla, F. Molinari, I. Rimoldi submitte
Artificial metalloenzymes based on vancomycin for stereoselective catalysis in aqueous media
Full text linkBackground: Artificial metalloenzymes, stemming from the combination of transition metal catalysts embedded within a biological environment, have recently risen up as a promising approach to merge the reactivity of metal-based catalysis and the specificity of biocatalysis. Dalbapeptides, such as vancomycin, teicoplanin and ristocetin are variously substituted heptapeptides whose antibiotic activity depends on their binding to the D-Ala-D-Ala dimer of peptidoglycan precursors thus resulting in the inhibition of cell wall biosynthesis. In this system, indeed, the source of chirality is due to the presence not only of the aminoacidic chain, but also from the atropoisomerism of their structure. This interaction is stabilized by an array of hydrophobic interactions and five key hydrogen bonds and it is marked by such a low dissociation constant (KD = ~10-17 M).
Objective: starting from this background, dalbapeptides can be employed as an innovative alternative to the classical biotin/(strept)avidin second sphere coordination system.
Methods: In this context, aminoethylbenzensulfonamide ligands decorated with the D-Ala-D-Ala dimer at different positions of the phenyl ring were employed for the synthesis of the hybrid catalysts in association with an iridium centre. In the presence of vancomycin, a new class of artificial reductases was obtained and applied to the stereoselective synthesis of chiral cyclic in different aqueous media.
Results: An encouraging 48% (S) e.e. was obtained in the asymmetric reduction of the salsolidine precursor in NaOAc 0.1 M buffer at pH 5 whereas in the case of the most demanding isoquinoline substrates, the meta-artificial metalloenzyme afforded the product in an outstanding 71% (S) e.e. when applied to quinaldine.
Conclusion: The Van/ D-Ala-D-Ala dimer system resulted particularly sensitive to pH variations, thus indicating an interesting change in the conformational arrangement of Van. Indeed, the system shows remarkable potential for the synthesis of chiral sultam precursors under green reaction conditions
New platinum-based chemotherapeutics: a journey beyond cisplatin
Full text linkThe discovery of cisplatin and its later approved derivatives started a new era in the bioinorganic medicinal chemistry field but the persistence of severe side-effects along with the emerging of drug resistance evoke the need of a new generation of transition metal-based chemotherapeutics. The starting point of this journey was the preparation of diamine ligands derived from variously substituted N-methyl-2-aminomethyl imidazoles.1 By introducing differently-long saturated and unsaturated chains at N1, the lipophilicity and the consequent cytotoxicity of the corresponding Pt(II)-complexes was modulated whereas its substitution with the 1,2,5-oxadiazole moiety selectively introduced the ability to simultaneously interact with DNA and to interrupt STAT3 signalling pathway.2 Breaking the assumption that bifunctionality is necessary for antiproliferative activity, a series of monofunctional cationic platinum complexes were synthesised showing a potent cytotoxic effect toward triple-negative breast cancer cells and in cancer cell lines partially resistant to cisplatin. Moreover, the prominent stability of this class of platinum complexes suggested also a possible application for MSCs loading to use for advanced cell therapy.3 Moving forward in this field, the effect of the bidentate ligands on the biological activity was highlighted showing for the Pt-8-aminoquinoline series a different biological profile.4 In order to gain some mechanistic insights, the interaction of such platinum-based compounds with some model proteins was investigated through ESI-MS analysis.
Since an increasing interest has recently arisen in the development of platinum based theranostic agents, indeed, a series of cyclometalated anionic Pt(II) complexes carrying tetrabromocatechol or alizarine as O^O chelating ligands was developed. This last series of platinum complexes displayed enhanced cytotoxicity toward triple-negative breast cancer (TNBC) and they furthermore resulted emissive in solution.5 Moreover, fluorescence confocal analysis showed their localization in the perinuclear region of MDA-MB231 cells proving their ability to serve as luminescent theranostic probes
New artificial imine reductases based on an iridium/ vancomycin system for the asymmetric reduction of cyclic imines
No full textArtificial metalloenzymes, deriving from transition metal catalysts embedding within a biological environment, have recently risen up as a promising synthetic tool able to combine the reactivity of metal-based catalysis with the specificity of biocatalysis.1 Dalbapeptides, such as vancomycin, teicoplanin and ristocetin are variously substituted heptapeptides whose antibiotic activity relies on their binding to the D-Ala-D-Ala dimer of peptidoglycan precursors thus leading to an irreversible inhibition of cell wall biosynthesis. This interaction is marked by such a low dissociation constant (KD =~10-17M) that it makes vancomycin-based systems an innovative alternative to the classical biotin/(strept)avidin technology.2,3
In this context, a class of aminoethylbenzensulfonamide ligands functionalized with the D-Ala-D-Ala dimer were employed for the synthesis of hybrid catalysts in association with an iridium centre. In the presence of vancomycin, a new class of artificial reductases was obtained and applied to the Asymmetric Transfer Hydrogenation (ATH) of model imine substrates in different aqueous media. An encouraging 48% (S) e.e. was obtained in the asymmetric reduction of the salsolidine precursor in CH3COONa 0.1 M buffer at pH 5 whereas in the case of quinolines, the meta-artificial metalloenzyme afforded the product in a significant 70% (S) e.e. when applied to quinaldine. Moreover, an unprecedented 35% (R) e.e. in the enantioselective reduction of chiral sultam precursor 3-methylbenzo[d]isothiazole-1,1-dioxide was realized under green reaction conditions
In vitro anticancer activity evaluation of new cationic platinum(II) complexes based on imidazole mojety
No full textPlatinum based-drugs currently used in therapy, i.e. cisplatin and its second and third generation derivatives carboplatin and oxaliplatin, were established to elicit their cytotoxic effect through the formation of bifunctional intra- and interstrand DNA adducts at the guanosine residues.
Since the discovery of the potent antiproliferative activity of the platinum triamine complex phenanthriplatin and of its analogues, the mechanism of action of monofunctional platinum compounds as anticancer agents have been deeply investigated.1,2
This class of platinum complexes bearing only one labile ligand is able to form only a single covalent bond at the N7 position of guanine residues without significantly bending or unwinding the double helix but indeed forming lesions of such a shape that result able to elude cellular repair responses and to potentially interact with other-than-DNA targets, thus affording a novel activity profile.
Starting from those assumptions and considering the promising results obtained of our research group in the synthesis of aminomethylimidazole based dichloride platinum complexes,3 we synthesised a series of cationic triamine platinum compounds of general formula [Pt(N-N’)N’Cl]X- where N-N’ is an aminomethylimidazole ligand and the N’ an imidazole ring, both bearing the same alkyl group at the N1 position. The resulting platinum complexes were analytically characterized and biologically evaluated on different cancer cell lines known for their aggressive behaviour (triple negative breast cancer)4 and for their poor sensitivity to the common cisplatin chemotherapy. Moreover, several in vitro assays were performed in order to better define their antitumor activity and target selectivity
Aminoquinoline-based Ruthenium catalyst for reduction of ketones by hydrogen transfer
No full text1. Introduction
Asymmetric reduction of C=O and C=N bonds to give chiral alcohols and amines is one of the more relevant applications of transition metal catalysis [1]. A striking improvement in hydrogenation or reduction by hydrogen transfer is due to Noyori and more recently to Rigo and co-workers with the development of Ru(II) catalysts bearing chiral diamine ligands [2].
2. Results and Discussion
Here we present our results in hydrogen transfer reduction of aryl ketones with (S)- or (R)-8-amino-5,6,7,8-tetrahydroquinoline (hereafter defined CAMPY).
The diphoshines (the counter ligands) used are the achiral triphenylphosphine, DPPB, DPPP and chiral BDPP, BDPH and Zedphos [3]. CAMPY is characterized by the presence of a fused ring; we will discuss the effects of such rigidity on matching/mismatching with the chiral diphosphines and the chirality at the metal centre on both enantioselectivity and activity.
3. References
[1] Asymmetric Catalysis on Industrial scale; H.U.Blase, E.Schmidt Eds, Wiley-VCH 2004
[2] P.Rigo, W.Baratta; Eur.J.Inorg.Chem. 2008, 4041.
[3] E.Cesarotti, I.Rimoldi, P.Spalluto, F.Demartin; Tetrahedon: Asimmetry, 2007, 1278
Aminophosphonite-phosphite and aminophosphonite-phosphinite ligands with mixed chirality: preparation and catalytic applications in asymmetric hydrogenation and hydroformylation
No full textAminophosphonite-phosphite and aminophosphonite-phosphinite chiral ligands with mixed stereogenic elements have been prepared in good yields from chiral α-aminoalcohols such as 2-(hydroxymethyl)pyrrolidine and 2-N-ethylammino-1-butanol. These new ligands have been fully characterized; the Rh(I) complexes have been tested in catalytic hydrogenation and hydroformylation reactions. Enantioselectivities up to 70% have been obtained in asymmetric hydrogenation of α-acetamidocinnamic acid, methyl ester; enantioselectivities higher than 30% and regioselectivities higher than 98% have been obtained in asymmetric hydroformylation of vinyl acetate
1,4-bis-difosfino-(Z)-2-buteni, 1,4 disostituiti otticamente puri in qualità di leganti chirali per la catalisi omogenea stereocontrollata con metalli di transizione
No full textLa presente invenzione ha come oggetto leganti 1,4 difosfinici chirali con due stereocentri uniti da un ponte etilenico in grado di coordinare stabilmente un metallo di transizione dando accesso a catalizzatori facilmente ottenibili con alte rese e altrettanto facilmente conservabili e utilizzabili.Come verrà illustrato in seguito, i leganti oggetto dell’invenzione uniscono due caratteristiche essenziali nella loro struttura: una grande rigidezza conformazionale tipica dei leganti a chiralità atropisomerica, dovuta alla presenza di un doppio legame carbonio-carbonio, e una grande flessibilità di sintesi tipica dei leganti con atomi di carbonio stereogenici
Catalytic strategies for the synthesis of carnosine derivatives
Full text linkL-Carnosine is a naturally occurring endogenous dipeptide formed by the combination of β-alanine and L-histidine, particularly in tissues with high oxidative metabolism such as muscles and the brain. By neutralizing free radicals and reducing oxidative stress—factors associated with various age-related conditions—it is believed to offer cellular protection1. The Global L-Carnosine Market size was estimated to be around USD 35.87 million in 2022, with projections indicating future growth at a compound annual growth rate of 6.45% until 2030. Thus, the development of synthetic methods able to afford L-Carnosine and its derivatives in enantiopure form is attracting interest and investments from both academia and industry. The contribution offers both the points of view applied to the attempt to achieve such a goal. The first part was focused on the development of a second-generation process for the synthesis of L-Carnosine. A series of nitrile precursor reduction studies was performed utilized gaseous H2 and commercially available (Pd, Rh, etc). As final scope, the optimization of the reaction conditions was performed, including a method for the isolation of the product as chromatographic separation and/or crystallization of the corresponding salt. Asymmetric hydrogenation using transition metal catalysts is a significant transformation in both academia and industry. Its high efficiency, atom economy, and broad substrate scope make this methodology appealing for both fields. In the second part, starting from an unsaturated precursor, different rhodium catalysts based on non-commercially available diphosphine were applied to the synthesis of enantiopure L-Carnosine derivatives with e.e. up to 95%
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