Regioselective and stoichiometrically controlled conjugation of photodynamic sensitizers to a HER2 targeting antibody fragment

The rapidly increasing interest in the synthesis of antibody–drug conjugates as powerful targeted anticancer agents demonstrates the growing appreciation of the power of antibodies and antibody fragments as highly selective targeting moieties. This targeting ability is of particular interest in the area of photodynamic therapy, as the applicability of current clinical photosensitizers is limited by their relatively poor accumulation in target tissue in comparison to healthy tissue. Although synthesis of porphyrin–antibody conjugates has been previously demonstrated, existing work in this area has been hindered by the limitations of conventional antibody conjugation methods. This work describes the attachment of azide-functionalized, water-soluble porphyrins to a tratuzumab Fab fragment via a novel conjugation methodology. This method allows for the synthesis of a homogeneous product without the loss of structural stability associated with conventional methods of disulfide modification. Biological evaluation of the synthesized conjugates demonstrates excellent selectivity for a HER2 positive cell line over the control, with no dark toxicity observed in either case

A Perspective on Recent Advances in Phosphorene Functionalization and its Application in Devices

Phosphorene, the 2D material derived from black phosphorus, has recently attracted a lot of interest for its properties, suitable for applications in material science. In particular, the physical features and the prominent chemical reactivity on its surface render this nanolayered substrate particularly promising for electrical and optoelectronic applications. In addition, being a new potential ligand for metals, it opens the way for a new role of the inorganic chemistry in the 2D world, with special reference to the field of catalysis. The aim of this review is to summarize the state of the art in this subject and to present our most recent results in preparation, functionalization and use of phosphorene and its decorated derivatives. In particular, we discuss several key points, which are currently under investigation: the synthesis, the characterization by theoretical calculations, the high pressure behaviour of black phosphorus, as well as decoration with nanoparticles and encapsulation in polymers. Finally, device fabrication and electrical transport measurements are overviewed on the basis of recent literature and new results collected in our laboratories

Catalytic polymeric nanoreactors : more than a solid supported catalyst

Polymeric nanostructures can be synthesized where the catalytic motif is covalently attached within the core domain and protected from the environment by a polymeric shell. Such nanoreactors can be easily recycled, and have shown unique properties when catalyzing reactions under pseudohomogeneous conditions. Many examples of how these catalytic nanostructures can act as nanosized reaction vessels have been reported in the literature. This prospective will focus on the exclusive features observed for these catalytic systems and highlight their potential as enzyme mimics, as well as the importance of further studies to unveil their full potential

Towards a Sequential One-Pot Preparation of 1,2,3-Benzotriazin-4(3H)-ones Employing a Key Cp*Co(III)-catalyzed C-H Amidation Step

1,2,3‐benzotriazin‐4(3H)‐one derivatives have been recognised for their potential application as pesticides and pharmaceuticals and new methodologies for their preparation, starting from readily accessible reagents would therefore be an attractive proposition. A wide range of differently substituted benzamides are readily available, which provide an excellent substrate scaffold for the application of direct C‐H functionalization protocols. In this context, herein we report the use of a Cp*Co(III) catalyst for the amidation of these benzamides, using 1,4,2‐dioxazol‐5‐ones as amidating agent. The isolable intermediate 2‐ acetamido benzamide products can thereafter be converted to to the desired 1,2,3‐benzotriazin‐4(3H)‐one derivatives through the use of tert‐butyl nitrite under mild conditions. It was found to be possible to perform the second step with the crude reaction mixture obtained from the initial C‐H amidation step, leading to the overall development of a facile one‐pot procedure for the preparation of a range of substituted 1,2,3‐benzotriazin‐4(3H)‐one derivatives, requiring only 5 hours of reaction time, which is also applicable on a gram scale. In addition, the key Cp*Co(III)‐catalyzed C‐H amidation step has been studied by DFT calculations in order to fully elucidate the mechanism

Direct introduction of nitrogen and oxygen functionality with spatial control using copper catalysis.

Synthetic chemists have spent considerable effort optimizing the synthesis of nitrogen and oxygen containing compounds through a number of methods; however, direct introduction of N- and O-functionality remains challenging. Presented herein is a general method to allow for the simultaneous installation of N- and O-functionality to construct unexplored N-O heterocyclic and amino-alcohol scaffolds. This transformation uses earth abundant copper salts to facilitate the formation of a carbon-centered radical and subsequent carbon-nitrogen bond formation. The intermediate aminoxyl radical is terminated by an intramolecularly appended carbon-centered radical. We have exploited this methodology to also access amino-alcohols with a range of aliphatic and aromatic linkers

Atom Transfer Radical Reactions as a Tool for Olefin Functionalization : On the Way to Practical Applications

Transition-metal-catalyzed atom transfer radical reactions of halogenated compounds with olefins constitute a versatile tool in organic synthesis within the area of C–C bond forming transformations. The inter- or intramolecular versions, atom transfer radical addition (ATRA) or cyclization (ATRC), respectively, lead to the atom-economic, useful synthesis of compounds that can be further functionalized. This contribution summarizes the recent developments in this area in terms of catalyst design as well as the applicability of this methodology in sequential, domino, or tandem reactions.We thank the Ministerio de Ciencia e Innovacion (grants CTQ2008-00042BQU and CTQ2008-06866-CO2-02/BQU), Consolider Ingenio 2010 (CSD2006-0003), and the Junta de Andalucia (Grant P07-FQM-02794) for financial support

Synthesis and properties of Poly(L-lactide)-b-poly (L-phenylalanine) hybrid copolymers

Hybrid materials constituted by peptides and synthetic polymers have nowadays a great interest since they can combine the properties and functions of each constitutive block, being also possible to modify the final characteristics by using different topologies. Poly(L-lactide-b-L-phenylalanine) copolymers with various block lengths were synthesized by sequential ring-opening polymerization of L-lactide and the N-carboxyanhydride of L-phenylalanine. The resulting block copolymers were characterized by NMR spectrometry, IR spectroscopy, gel permeation chromatography, MALDI-TOF and UV-vis, revealing the successful incorporation of the polyphenylalanine (PPhe) peptide into the previously formed poly(L-lactide) (PLLA) polymer chain. X-ray diffraction and DSC data also suggested that the copolymers were phase-separated in domains containing either crystalline PLLA or PPhe phases. A peculiar thermal behavior was also found by thermogravimetric analysis when polyphenylalanine blocks were incorporated into polylactide.Peer ReviewedPostprint (published version

Remodelling of the natural product fumagillol employing a reaction discovery approach

In the search for new biologically active molecules, diversity-oriented synthetic strategies break through the limitation of traditional library synthesis by sampling new chemical space. Many natural products can be regarded as intriguing starting points for diversity-oriented synthesis, wherein stereochemically rich core structures may be reorganized into chemotypes that are distinctly different from the parent structure. Ideally, to be suited to library applications, such transformations should be general and involve few steps. With this objective in mind, the highly oxygenated natural product fumagillol has been successfully remodelled in several ways using a reaction-discovery-based approach. In reactions with amines, excellent regiocontrol in a bis-epoxide opening/cyclization sequence can be obtained by size-dependent interaction of an appropriate catalyst with the parent molecule, forming either perhydroisoindole or perhydroisoquinoline products. Perhydroisoindoles can be further remodelled by cascade processes to afford either morpholinone or bridged 4,1-benzoxazepine-containing structures.P50 GM067041 - NIGMS NIH HHS; P50 GM067041-07 - NIGMS NIH HHS; P50 GM067041-08 - NIGMS NIH HHS; P50 GM067041-09 - NIGMS NIH HH