Development of free radical methodology for natural products synthesis

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Construction of a 3D-shaped, natural product like fragment library by defragmentation and diversification of natural products

A fragment library consisting of 3D-shaped, natural product-like fragments was assembled. Library construction was mainly performed by natural product degradation and natural product diversification reactions and was complemented by the identification of available 3D-shape and natural product like fragments from the available commercial sources. During the course of these studies, a novel rearrangement was discovered for Massarigenin C. The obtained fragment library has an excellent 3D-shape and natural product likeness, covering an underexplored and underrepresented chemical space in fragment based drug discovery (FBDD)

Construction of a 3D-shaped, natural product like fragment library by fragmentation and diversification of natural products

A fragment library consisting of 3D-shaped, natural product-like fragments was assembled. Library construction was mainly performed by natural product degradation and natural product diversification reactions and was complemented by the identification of 3D-shaped, natural product like fragments available from commercial sources. In addition, during the course of these studies, novel rearrangements were discovered for Massarigenin C and Cytochalasin E. The obtained fragment library has an excellent 3D-shape and natural product likeness, covering an underexplored and underrepresented chemical space in fragment based drug discovery (FBDD)

Total Synthesis and Biological Evaluation of Halipeptins A and D and Analogues.

The marine-derived halipeptins A (1a) and D (1d) and their analogues 3a, 3d and 4a, 4d were synthesized starting from building blocks 10, 13, 14a or 14d, 15, and 16. The first strategy for assembling the building blocks, involving a macrolactamization reaction to form the 16-membered ring hydroxy thioamide 52d as a precursor, furnished the epi-isoleucine analogue (4d) of halipeptin D, whereas a second approach involving thiazoline formation prior to macrolactamization led to a mixture of halipeptins A (1a) and D (1d) and their analogues 3a, 3d (epimers at the indicated site) and 4a, 4d (epimers at the indicated site). The same route starting with D-Ala resulted in the exclusive formation of the epimeric halipeptin D analogue 3d. The synthesized halipeptins, together with the previously constructed oxazoline analogues 5d and 6d, were subjected to biological evaluation revealing anti-inflammatory properties for la, 1d, and 6d while being noncytotoxic against human colon cancer cells (HCT-116)

Bioorthogonal Probes to study MDM2-p53 inhibitors in cells and to develop high content screening assays for drug discovery

To study the behavior of MDM2-p53 inhibitors in a disease-relevant cellular model, we have developed and validated a set of bioorthogonal probes that can be fluorescently labeled in cells and used in high content screening assays. Using automated image analysis and single cell resolution, we could visualize the intracellular target binding of compounds by co-localization and quantify target upregulation upon MDM2-p53 inhibition in an osteosarcoma model. In addition, we developed a high throughput assay to quantify target occupancy of non-tagged MDM2-p53 inhibitors by competition and to identify novel chemical matter. This approach could be expanded to other targets for lead discovery applications

1,4-pentadienyl-3-sulfonamides: Frameworks for disfavored radical cascade cyclizations

1,4-Pentadienyl-3-sulfonamides afford products including those resulting from disfavored 5-endo-trig reactions when subjected to radical cyclization conditions. Products resulting from pathways featuring 4-exo-trig cyclizations are also detected, even when the 4-exo-trig reaction leads to a highly strained bicyclo[3.2.0] ring system