Davide Bini

Pyrrolo(2,1-c)(1,4)benzodiazepine as a Scaffold for the Design and Synthesis of Anti- Tumour Drugs

Compounds that bind in the minor groove of DNA have found use in the experimental treatment of cancer and certain infectious diseases. Furthermore, agents which target and can recognize discrete sequences of DNA have the potential to offer selective therapies by modulating the activity of specific transcription factors or genes. For this reason, a number of sequence-selective DNA binding agents have been evaluated with a range of affinities and recognition fidelities. In this respect, the pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are of interest as they bind to guanine residues in the minor groove with a preference for Pu-G-Pu sequences. A dramatic increase in cytotoxicity and sequence selectivity has been achieved by linking two PBD units to form PBD dimers as cross-linking agents on opposite DNA strands (e.g., interstrand cross-links). SJG-136 is currently undergoing Phase I evaluation in both the United States (through the NCI) and United Kingdom (through Cancer Research United Kingdom). This review will focus on design, synthesis and structure activity relationship studies of pyrrolobenzodiazepines as anticancer therapeutics reported since 2003.

Discovery and design of carbohydrate-based therapeutics

Importance of the field: Till now, the importance of carbohydrates has been underscored, if compared with the two other major classes of biopolymers such as oligonucleotides and proteins. Recent advances in glycobiology and glycochemistry have imparted a strong interest in the study of this enormous family of biomolecules. Carbohydrates have been shown to be implicated in recognition processes, such as cell–cell adhesion, cell–extracellular matrix adhesion and cell–intruder recognition phenomena. In addition, carbohydrates are recognized as differentiation markers and as antigenic determinants. Due to their relevant biological role, carbohydrates are promising candidates for drug design and disease treatment. However, the growing number of human disorders known as congenital disorders of glycosylation that are being identified as resulting from abnormalities in glycan structures and protein glycosylation strongly indicates that a fast development of glycobiology, glycochemistry and glycomedicine is highly desirable. Areas covered in this review: The topics give an overview of different approaches that have been used to date for the design of carbohydrate-based therapeutics; this includes the use of native synthetic carbohydrates, the use of carbohydrate mimics designed on the basis of their native counterpart, the use of carbohydrates as scaffolds and finally the design of glyco-fused therapeutics, one of the most recent approaches. The review covers mainly literature that has appeared since 2000, except for a few papers cited for historical reasons. What the reader will gain: The reader will gain an overview of the current strategies applied to the design of carbohydrate-based therapeutics; in particular, the advantages/disadvantages of different approaches are highlighted. The topic is presented in a general, basic manner and will hopefully be a useful resource for all readers who are not familiar with it. In addition, in order to stress the potentialities of carbohydrates, several examples of carbohydrate-based marketed therapeutics are given. Take home message: Carbohydrates are a rich class of natural compounds, possessing an intriguing and still not fully understood biological role. This richness offers several strategies for the design of carbohydrate-based therapeutics.

Kdo: a critical monosaccharide for bacteria viability

Covering: 2000 to 2010 Kdo belongs to the 3-deoxysugar ‘family’ and is a critical monosaccharidic component of lipopolysaccharides (LPSs) in Gram-negative bacteria. The incorporation of Kdo into LPSs is a vital step in the assembly of the protective outer membrane of Gram-negative bacteria. This review intends to present recent advances on structural/biocatalytic knowledge on the four enzymes involved in Kdo metabolism, and on the synthesis and biological activity of analogues of biosynthetic intermediates, highlighting the potential of this pathway for the discovery of new antibacterials – a pressing need due to the emergence of new classes of antibiotic-resistant bacteria.

Synthesis and biological evaluation of nojirimycin- and pyrrolidine-based trehalase inhibitors

Summary A small set of nojirimycin- and pyrrolidine-based iminosugar derivatives has been synthesized and evaluated as potential inhibitors of porcine and insect trehalases. Compounds 12, 13 and 20 proved to be active against both insect and porcine trehalases with selectivity towards the insect glycosidase, while compounds 10, 14 and 16 behaved as inhibitors only of insect trehalase. Despite the fact that the activity was found in the micromolar range, these findings may help in elucidating the structural features of this class of enzymes of different origin, which are still scarcely characterised.

Dendron synthesis and carbohydrate immobilization on a biomaterial surface by a double-click reaction.

The synthesis of new dendrons and their immobilization on collagen patches via thiol-ene photoclick reaction, followed by chemoselective alkoxyamino-carbonyl conjugation to carbohydrates is presented. XPS, FTIR, and ELLA assays confirmed the effectiveness of the collagen multivalent neoglycosylation.

Recent approaches to novel antibacterials designed after LPS structure and biochemistry.

Lipopolysaccharides (LPSs), which constitute the lipid portion of the outer leaflet of Gram-negative bacteria, are essential for growth, and are responsible for a variety of biological effects associated with Gram-negative sepsis. LPSs are amphiphilic molecules comprising three regions: lipid A, the core region, and a polysaccharide portion; the lipid A was proven to represent the toxic principle of endotoxic active lipopolysaccharides. In addition, it is known that the minimal conserved structure of LPS is the lipophylic oligoasaccharidic structure containing Kdo residues linked to the-LipA moiety. Thus, the design and development of novel antibacterial drugs can focus on different aspects, related to the biosynthesis and chemical features of LPS: 1) Inhibitors of lipid A biosynthesis 2) Inhibitors of Kdo biosynthesis. Both Kdo and Lipid A are needed for the construction of the minimum structural element Kdo2-LipidA, needed for bacterial survival. Any inhibitors acting on the biogenetic pathway of this molecule can act as antibacterial. 3) Antagonists of the interaction between endotoxins and the host receptors: LPS is recognised by the CD14 and the Toll-like receptor (TLR)-4/MD2 complex, where Lipid A is the crucial moiety in the interaction. Any drug acting as an antagonist of this process can have antisepsis potential. Considerable efforts have been made in this direction to identify natural or synthetic molecules able to interfere with the interaction between LPS and inflammatory cells. This review will highlight recent efforts in the design and biological activity of enzyme inhibitors and antagonist acting on the 3 key aspects outlined above.

N-Bridged 1-deoxynojirimycin dimers as selective insect trehalase inhibitors

A small set of N-bridged 1-deoxynojirimycin dimers has been synthesized and evaluated as potential inhibitors of insect trehalase from midge larvae of Chironomus riparius, porcine trehalase as the mammalian counterpart and α-amylase from human saliva. All the tested compounds (2-4) proved to be active (micromolar range activity) against insect trehalase, showing selectivity toward the insect glycosidase. No activity was observed against α-amylase.

Smart biomaterials: the contribution of glycoscience

Examples of material functionalisation (“biodecoration”) with signalling and relevant glycidic scaffolds will be outlined. Recent research concerning the development of smart biomaterials for Tissue Engineering (TE) applications will be considered.

Synthesis and characterization of a paramagnetic sialic acid conjugate as probe for magnetic resonance applications.

Magnetic Resonance Imaging (MRI) using paramagnetic systems as contrast agents is receiving increased attention as diagnostic tool in the clinic. At the same time, NMR of paramagnetic systems can also be applied in biochemical fields; for example, the use of Paramagnetic Relaxation Enhancement (PRE) allows structure refinement and the analysis of transient dynamic processes involved in macromolecular complex formation. Herein we report the synthesis and computational characterization of a new DOTA-like sialic acid conjugate, which can be used both in MRI and PRE applications when coordinated to a suitable paramagnetic metal.

Chapter 10:Trehalose mimetics as inhibitors of trehalose processing enzymes

Trehalose has been studied for more than a hundred of years, but its biochemical and physico-chemical properties are still far from being fully understood, despite the abundance of published data. A huge number of publications has recently appeared on trehalose functions and properties, and many rev...