Exploiting activated esters in novel chemoselective amide formation reactions

Detailed within this thesis are the synthetic studies performed on the preparation of lipase catalysed activated esters and their subsequent use in the synthesis of pharmaceutically relevant amides. It also includes the application of activated esters in chemoselective amide formation reactions. The introduction summarizes the significance and use of activating agents in lipase catalysed reactions over the classical methods of amides synthesis. Additionally, a detailed review on some currently available chemoselective N-acylating agents along with their applications is also mentioned. A separate chapter is given to the application of related amides in the designing of biological probes to ultimately detect enzymes which are over-expressed in disease. The discussion begins with the lipase-catalysed synthesis of acetone oxime activated esters and their role in the one-pot synthesis of acetanilides. Further discussion continues with the synthesis of activated esters from ethylene glycol and haloalcohols. The use of a lipase in the synthesis of glycol esters prevented the formation of dimers which indicates its potential usefulness in the future. Unfortunately, these activated esters could not be applied to a synthesis of amides in the same manner as acetone oxime. Thereafter the section focuses on the investigation and synthesis a novel chemoselective N-acylating agent and its subsequent applications in the synthesis of pharmaceutically important amides, in particular, those involving chemoselective reactions between anilines and N-substituted anilines. Additionally, the chemoselective agent was also used in preparation of pharmaceutically important compounds. To round off the thesis the application of one of the target compounds-benzanilide-was used to develop and synthesise a novel biological probe and to scope out its potential for application in the detection of enzyme-controlled disease. The preliminary utility of the probe was demonstrated using HPLC and NMR. The thesis concludes with the experimental encompassing experimental details, spectroscopic and analytical analysis of all the compounds described

Aromatic amides and ureas as novel molecular probes for diagnosing disease

It is firmly established that control over the three-dimensional shape (i.e., the conformation) of aromatic amides and ureas can be achieved using a variety of methods, all of which rely on the addition of a substituent to a central nitrogen atom; exactly which conformation is adopted in solution can be determined using a variety of analytical techniques, such as: fluorescence, NMR and HPLC. We hypothesise that if the central nitrogen atoms were suitably functionalised with enzyme-cleavable groups, then the associated change in shape could be exploited upon the removal of a group, and these compounds could thus be exploited as diagnostic probes for the detection of analytes (i.e., enzymes) in solution or biological samples. The exquisite selectivity of naturally-occurring enzymes therefore makes it possible that the enzyme-cleavable group could be rationally designed and tailored for each enzyme of interest, thus making an analytical toolkit of diagnostic probes for detecting enzymes which are over-expressed in disease. If the sensitivity of such probes was sufficiently low enough, then they could potentially be used to detect the on-set of disease in a non-invasive manner from bodily fluids

A therapeutic update on PARP inhibitors: implications in the treatment of glioma

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Central nervous system (CNS) cancers are among the most aggressive and devastating. Furthermore, because of the lack of neuro-oncologists and neurosurgeons in many parts of the world, the specialized treatment options of CNS cancers are not fully available worldwide. Among various strategies of inducing death in cancer cells, inhibition of poly(ADP-ribose)polymerase (PARP) has emerged as a beneficial therapy when combined with other anticancer agents. In this review, we provide a detailed therapeutic update of PARP inhibitors (PARPis) that have shown clinical activity against glioma

2,3-Diarylindoles as COX-2 Inhibitors: Exploring the Structure-activity Relationship through Molecular Docking Simulations

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI linkBackground: Arylindole derivatives are promising scaffolds in the design of new drugs, including inhibition of COX-2, antitumor activity, receptor GABA agonism, and estrogenic receptor modulation. Objective: Taking this into account, this paper presents a study to better understand the inhibitory action of certain 2-arylindole derivatives, specifically a series of 2,3-diarylindoles with IC50 values from 0.006 nM to 100 nM on the COX-2 enzyme and supports its structural-activity relationship (SAR) through molecular docking simulations. Methods: Briefly, the ligands’ three-dimensional models were drawn, and the conformational analysis was accessed in the Chem3D 19.1 program (PerkinElmer). After different steps of parametrizations, the lowest energy conformations were selected for the molecular docking simulation, which used the crystal structure of human COX-2 in complex with meclofenamic acid to 2.4 Å resolution (PDB code 5IKQ) as molecular target. Results: The results indicated that Gly 526 and Phe 381 residues are relevant for the improvement of inhibitory activity on para-substituted 3-phenyl- compounds. Arg 120 was also demonstrated to be an important residue for COX-2 inhibition, since it is involved in enabling a π-cation interaction with the best compound in series A5 (experimental IC50 = 0.006 nM determined in advance). Furthermore, COX-2 presents flexibility in some regions of the active site to adequately accommodate 5-substituted compounds containing an indole ring. Conclusion: Such structural features can be used as support for further Structural-Based Drug Design (SBDD) and/or Ligand-Based Drug Design (LBDD) studies of new selective COX-2 inhibitors