Development of methods toward the synthesis of novel bioactive natural product-like scaffolds

Abstract

The complexity and inherent biological relevance of natural products (NPs) are key characteristics that have made them a constant source of inspiration in the development of novel bioactive compounds. However, NPs alone cannot solve the lack of diverse chemical scaffolds extending into unexplored chemical and biological space. As a result, this has led to innovative reaction methodology and design strategies being used to deliver new NP-like scaffolds. In this thesis, access to four different NP-like scaffolds, by means of unique reaction methodology (Chapter I) or the pseudo-NP design principle (Chapter II) will be discussed. A novel Rh(III)-catalysed C-H functionalisation reaction coupling N-Boc benzamides with ortho-substituted styrenes affording unique isoindolinone derivatives is disclosed in Chapter I. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the combination of the ortho-substituent on the styrene and the OBoc group of the benzamide. Furthermore, this scaffold was used to generate isoindolobenzazepine derivatives, via an additional SN2 reaction. Biological evaluation of selected compounds from both compound libraries revealed inhibitory activity in the Hedgehog (Hh)-dependent osteoblast differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts. The pseudo-NP approach is a strategy involving the de-novo combination of NP fragments in novel arrangements with the dual aim of targeting novel chemical and biologically relevant space. A new class of pseudo-NPs combining indole- and tetrahydropyridine (THP)-fragments in a novel arrangement is described in Chapter II. The monopodal connectivity between the fragments, not yet observed in nature, was facilitated by a phosphine-catalysed asymmetric [4+2] annulation reaction, to obtain the pseudo-NP scaffold. Biological screening in various cell-based assays revealed the pseudo-NPs to be potent in reducing cellular kynurenine levels. Further investigation identified the mode-of-action to be the selective targeting and stabilisation of apo-indoleamine 2,3-dioxygenase 1 (apo-IDO1), a therapeutic target enzyme involved in immuno-suppression, linked to numerous disorders including cancer. Additionally, this pseudo-NP class was used to obtain the final NP-like class, in the form of bridged-bicyclic compounds. The synthesis of the pseudo-NP class validated the design principle with regard to unexplored fragment arrangements providing a route to compound classes endowed with unexpected or new bioactivity.