Abstract
1,4-, 1,6- or 1,8-self immolative linkers have been employed as effective masking groups for pharmaceutical agents used in prodrug therapies. Upon activation, these structures release their payloads via their respective electron cascade mechanisms, with the generation of CO2 and a reactive intermediate compound called an azaquinone methide. These methides are powerful Michael accepting electrophiles and lead to off-target toxicity. Previous work within the Gamble group investigated the placement of a nucleophilic handle conveniently positioned to perform an intramolecular Michael addition to in-situ-generated methides. This work was, however, limited to the formation of 1,2,3,4-tetrahydroisoquinoline (THIQ) compounds 43 and 44. This thesis further develops these findings into a synthetic chemical method for the formation of various heterocyclic scaffolds – including THIQs – by investigating various amine nucleophiles, as well as oxygen and sulfur nucleophiles. Azaquinone methides were generated via nitro-containing acyclic precursors that were chemically activated with Zn/AcOH. Reduction in the mild-acidic and raised temperature conditions led to the loss of a water molecule from the resulting 4-aminobenzyl alcohol to generate an azaquinone methide.
Chapter 2 describes the synthesis of known and novel THIQ’s via a one-pot nitro reduction and cyclisation step. An optimised, novel synthesis of THIQ 44 was carried out, with a yield of 26% over eight steps, compared to 8% over six steps previously reported. A total of fourteen THIQ compounds were synthesised using this optimised procedure, with the yields of the final nitro reduction and cyclisation step ranging from 37% to 89%.
Chapter 3 describes how strategically placed anilino groups could be applied in the synthesis of 5,6-dihydrophenanthridine (5,6-DHPA) and phenanthridine compounds via acyclic biphenyl precursors and the subsequent trapping of the generated azaquinone methide. Phenanthridine 264 formed with a yield of 46% over six steps, and a total of four phenanthridine or 5,6-DHPA compounds were synthesised. These findings were expanded upon with the investigation into coupling a model drug (7-hydroxycoumarin) and analysing the release of this model drug and the intramolecular cyclisation of a 5,6-DHPA scaffold via a proof-of-concept study using HPLC conditions previously optimised within the Gamble group.
Chapter 4 describes the expansion of the ring size in the heterocycle formed via the intramolecular cyclisation of a secondary benzylamine with an azaquinone methide. A 2,3,4,5-tetrahydrobenzoazepine (THBA) 313 was produced in 92% yield as a proof-of-concept, and investigations into the formation of a 2,3-dihydrobenzoazepine (DHBA) 323 were conducted, however, the formation of a cis-alkene proved to be difficult. Chapter 4 also investigated non-amine nucleophiles with heterocycles formed from a primary alcohol 66, disulfide dimer 368 and a hydrazide 380, affording isochromane 362, thioisochromane 364, and heterocycle 385 in 17%, 61% and 45% yield, respectively.
Overall, this thesis has produced high yielding synthetic methods for the synthesis of various heterocyclic scaffolds from acyclic precursors via azaquinone methide intermediates. Reductive triggering of the electron cascade and nucleophilic trapping of an azaquinone methide was reported, however, the structures of the acyclic precursors are adaptable and allow for other types of triggering events that have uses in both prodrug strategies and in general chemical synthesis. The work has generated a significant number of new ideas for the in-situ drug synthesis or late-stage heterocycle installation, thus Chapter 5 describes the future directions for this project, including the use of carbon-based nucleophiles