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Title: Reactions of sydnones toward pyrazole- and sydnone-based analogues of CA4P
Author: Brown, Andrew W.
ISNI:       0000 0004 5993 3120
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2016
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Sydnones represent versatile intermediates for the highly-regioselective synthesis of pyrazoles. The Buchwald ligand XPhos in conjunction with palladium catalysis facilitated the direct arylation of sydnones with aryl chlorides. Both N-aryl- and N-alkylsydnones were tolerated and the scope with respect to the aryl coupling partner was impressively broad. The combretastatins are a class of tumour Vascular Disrupting Agents (VDAs) that have shown promise in the clinic for cancer therapy. Sydnone-based analogues of the lead compound, combretastatin A4 (CA4) were successfully prepared using the newly-developed direct arylation methodology. The compounds were evaluated in vitro using human umbilical vein endothelial cells (HUVECs) and the most active exhibited moderately high activity. The most active compound, 58, was shown to activate the RhoA/ROCK pathway in a similar manner to CA4. 58 was phosphorylated to improve solubility and tested in vivo. However, the compound was completely inactive in the mouse model used. Sydnones were used to prepare pyrazole-based analogues of CA4 in a highly-regioselective manner. Each possible structural isomer around the pyrazole core was successfully synthesised. The direct arylation methodology developed earlier was integral to the synthesis of 1,5- and 4,5-disubstituted analogues. In addition, an interesting monofluoromethylation reaction was also discovered and mechanistic insights obtained. Similarly to sydnone analogues, the compounds were evaluated in vitro and exhibited modest to high activity. The most active compound, 85, appeared at least as potent as CA4 in all the cell-based assays conducted. 85 was then analysed in vivo, and instigated an apparent increase in tumour cell necrosis in the mouse model used. Furthermore, it appeared equipotent to CA4P in vivo. Directed cycloadditions offer a means to reduce the typically high temperatures and long reaction times required in dipolar cycloadditions. Typically, a Lewis acidic alkynylborane is generated in situ and paired with a Lewis basic directing group on the substrate. The methodology was successfully applied to sydnones with reaction temperatures decreased from 180 ?C for the thermal reaction to 25 ?C in the directed cycloaddition. Furthermore, reaction times were reduced to 2 hours from 48 hours in thermal reactions and afforded excellent yields of the pyrazole products. Interestingly, the sole products of the reactions were dialkynylboranes, which had only ever been observed as minor products in previous directed cycloadditions. The dialkynylboranes underwent typical reactions of organoboranes including oxidation and Suzuki-Miyaura coupling. Mechanistic studies were undertaken and provided some insight into the unusual aspects of the reaction.
Supervisor: Harrity, Joseph P. A. ; Kanthou, Chryso ; Tozer, Gillian M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Thesis
EThOS ID:  DOI: Not available