A5023881545- Monoclonal and Polyclonal Antibodies Research
- Cell Adhesion Molecules Research
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- RNA Interference and Gene Delivery
- HER2/EGFR in Cancer Research
- Chemical Synthesis and Analysis
- Radical Photochemical Reactions
- Protein Degradation and Inhibitors
- Radiopharmaceutical Chemistry and Applications
- Chemokine receptors and signaling
- Glycosylation and Glycoproteins Research
- Enzyme function and inhibition
- Dendrimers and Hyperbranched Polymers
- Protease and Inhibitor Mechanisms
- Histone Deacetylase Inhibitors Research
- Nanoplatforms for cancer theranostics
- Oxidative Organic Chemistry Reactions
- Phagocytosis and Immune Regulation
- Asymmetric Hydrogenation and Catalysis
- Lung Cancer Research Studies
- Advanced biosensing and bioanalysis techniques
- Sulfur-Based Synthesis Techniques
- Angiogenesis and VEGF in Cancer
- Catalytic C–H Functionalization Methods
University of Milan
2014-2024
ETH Zurich
2016-2023
Mylan (Switzerland)
2019-2021
We present the first direct comparative evaluation of an antibody–drug conjugate and a small molecule–drug for cancer therapy, using chemically defined products which bind with high-affinity to carbonic anhydrase IX, marker tumor hypoxia renal cell carcinoma.
Antibody–drug conjugates (ADCs) represent an attractive class of biopharmaceutical agents, with the potential to selectively deliver potent cytotoxic agents tumors. It is generally assumed that ADC products should preferably bind and internalize into cancer cells in order liberate their toxic payload, but a growing body evidence indicates also ADCs based on noninternalizing antibodies may be potently active. In this Communication, we investigated dipeptide-based linkers (frequently used for...
Abstract The discovery of protein ligands, capable forming a reversible covalent bond with amino acid residues on target interest, may represent general strategy for the potent small‐molecule inhibitors. We analyzed ability different aromatic aldehydes to form imines by reaction lysine using 1 H NMR techniques. 2‐Hydroxybenzaldehyde derivatives were found efficiently in millimolar concentration range. These benzaldehyde could increase binding affinity ligands towards cognate target. Affinity...
In most cases, cytotoxic drugs do not preferentially accumulate at the tumor site, causing unwanted toxicities and preventing dose escalation to therapeutically active regimens. Here, we show that acetazolamide derivatives, which bind carbonic anhydrase IX (CAIX) on surface of kidney cancer cells, selectively deliver payloads site disease, sparing normal organs. Biodistribution studies, performed in tumor-bearing mice with derivatives bearing a technetium-99m chelator complex or red...
Abstract Two small‐molecule–drug conjugates (SMDCs, 6 and 7 ) featuring lysosomally cleavable linkers (namely the Val–Ala Phe–Lys peptide sequences) were synthesized by conjugation of α v β 3 ‐integrin ligand cyclo [DKP–RGD]‐CH 2 NH ( to anticancer drug paclitaxel (PTX). A third [DKP–RGD]–PTX conjugate with a nonpeptide “uncleavable” linker 8 was also be tested as negative control. These three SMDCs able inhibit biotinylated vitronectin binding purified V receptor at nanomolar concentrations...
Self-immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)-2-(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either phenolic secondary and tertiary hydroxyl groups) through fast cyclization mechanism involving carbamate cleavage. The high efficiency drug obtained with this was found be beneficial the in vitro cytotoxic activity...
Abstract The cyclo [DKP‐ iso DGR] peptidomimetics 2 – 5 , containing bifunctional diketopiperazine (DKP) scaffolds that differ in the configuration of two DKP stereocenters and substitution at nitrogen atoms, were prepared examined vitro competitive binding assays with purified α v β 3 integrin receptors. IC 50 values ranged from low nanomolar (ligand ) to submicromolar integrin. biological activities ligands [DKP3‐RGD] 1 [DKP3‐ bearing same scaffold showing similar V values, compared terms...
The screening of encoded self-assembling chemical libraries allows the identification fragment pairs that bind to adjacent pockets on target proteins interest. For practical applications, it is necessary link these ligand into discrete organic molecules, devoid any nucleic acid component. Here we describe discovery a synergistic binding pair for alpha-1 glycoprotein and strategy optimal linkers, connecting two fragments. procedure yielded set small ligands, best which exhibited dissociation...
This work reports the synthesis of a series small-molecule-drug conjugates containing α
This work takes advantage of one the hallmarks cancer, that is, presence tumor infiltrating cells immune system and leukocyte-secreted enzymes, to promote activation an anticancer drug at site. The peptidomimetic integrin ligand cyclo(DKP-RGD) was found accumulate on surface αv β3 integrin-expressing human renal cell carcinoma 786-O cells. conjugated paclitaxel through a Asn-Pro-Val (NPV) tripeptide linker, which is substrate neutrophil-secreted elastase. In vitro linker cleavage assays...
Abstract This work reports the synthesis of three multimeric RGD peptidomimetic‐paclitaxel conjugates featuring a number α V β 3 integrin ligands ranging from 2 to 4. These constructs were assembled by conjugation ligand cyclo [DKP‐RGD]‐CH NH with paclitaxel via 2′‐carbamate self‐immolative spacer, lysosomally cleavable Val‐Ala dipeptide linker, scaffold, triazole linkage, and finally PEG spacer. Two monomeric also synthesized as reference compounds. Remarkably, new showed binding affinity...
A perfect fit: Shown here is the docking best pose of a low-nanomolar αvβ3 integrin ligand cyclo[DKP-isoDGR] (atom color tube representation; see figure) into receptor binding pocket, overlaid on bound conformation Cilengitide (green representation). The extended isoDGR permits all important interactions with extracellular domain integrin. metal ion in MIDAS region represented by magenta sphere. As service to our authors and readers, this journal provides supporting information supplied...
Abstract A dual‐action ligand targeting both integrin α V β 3 and vascular endothelial growth factor receptors (VEGFRs), was synthesized via conjugation of a cyclic peptidomimetic Arg‐Gly‐Asp (RGD) with decapentapeptide. The latter obtained from known VEGFR antagonist by acetylation at the Lys13 side chain. Functionalization precursor ligands carried out in solution solid phase, affording two fragments: an alkyne azide ligand, which were conjugated click chemistry. Circular dichroism studies...
High-affinity monovalent ligands for lectins are challenging to develop due weak binding interactions. This study investigates the potential of rationally designed covalent targeting N-terminal domain BC2L-C lectin from Burkholderia cenocepacia, a pathogen causing severe respiratory infections in immunocompromised patients. Antiadhesion therapy is emerging as complementary approach against such infections, and bacterial suitable targets. The fucose-specific BC2L-C-Nt recognizes blood group...
The rational design, synthesis and in vitro biological evaluation of dual action conjugates 11-13, containing a tumour targeting, integrin αvβ3/αvβ5 ligand portion pro-apoptotic SMAC mimetic (cyclo-RGD/SMAC conjugates) are reported. binding strength the two separate units is generally maintained by these conjugates. In particular, connection between (anchor points on each unit; nature, length stability linker) influences activity against its molecular targets (integrins for cyclo-RGD, IAP...
Abstract The discovery of protein ligands, capable forming a reversible covalent bond with amino acid residues on target interest, may represent general strategy for the potent small‐molecule inhibitors. We analyzed ability different aromatic aldehydes to form imines by reaction lysine using 1 H NMR techniques. 2‐Hydroxybenzaldehyde derivatives were found efficiently in millimolar concentration range. These benzaldehyde could increase binding affinity ligands towards cognate target. Affinity...
Abstract Amine‐carbamate self‐immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine‐carbamate SI spacer with tertiary amine handle which strongly accelerates cyclization to give bicyclic urea free hydroxy groups either cytotoxic (Camptothecin) or immunostimulatory (Resiquimod) drugs. In silico conformational analysis p K calculations suggest...
Two cyclo [DKP‐RGD]‐PTX (PTX = paclitaxel) and two [RGDfK]‐PTX conjugates containing the Gly‐Phe‐Leu‐Gly (GFLG) linker, which is cleavable by lysosomal enzymes, were synthesized compared to [DKP‐RGD]‐Val‐Ala‐PTX conjugates. The evaluated for their ability inhibit biotinylated vitronectin binding isolated α v β 3 receptor, retaining good affinity, in same nanomolar range of free ligands. Cell viability assays performed six + U87 – HT29 cell lines. Loss potency was observed all conjugates,...
Thanks to a highly active catalyst, the scope of (cyclopentadienone)iron complex-promoted ‘hydrogen-borrowing’ (HB) amination has been expanded secondary alcohols, which had previously reported react only in presence large amounts co-catalysts. A range cyclic and acyclic alcohols were reacted with aromatic aliphatic amines giving fair excellent yields substitution products. The catalyst was also able promote cyclization diols bearing alcohol group primary generate saturated N-heterocycles.