Synthesis of Indole Alkaloids: Natural Product and Target-Based Approaches

Abstract

Novel chemical structures offer interesting and challenging synthetic targets with those that are bioactive having the additional advantage of providing an ideal platform for the development of new drug leads. Therefore, the development of new therapeutic agents has been an area of significant scientific focus in efforts to not only combat emerging resistant microorganism caused diseases but also a large variety of cancers for which eliminative treatment is not available, thus leaving patients in many cases with only supportive care. The research presented herein concentrates on the attempted total synthesis of the cis-enamide containing indole alkaloid kottamide E 2.64 as well as the synthesis of a variety of other related compounds through either natural product or target-based directed approaches. Kottamide E 2.64 along with related kottamides A-D 2.60-2.63 represent novel chemical structures unseen before their isolation from the extracts of the marine ascidian Pycnoclavella kottae, sourced at the Three Kings Islands, New Zealand. Furthermore, these compounds show respectable anti-cancer activity particularly against leukaemia cells displaying inhibitory concentrations as low as 14 µM. Initially the synthesis of cis-indole enamides was attempted starting from simple N-unprotected indole alkynes by the insertion of primary amides using a ruthenium-catalysed hydroamidation as the key synthetic step. A range of N-protected indole alkynes were also synthesised to overcome problems associated with purification of products obtained using the unprotected substrates. Following this, the successful synthesis of several N-protected and deprotected analogues using natural amino acids was achieved and attempts were made towards the total synthesis of kottamide E 2.64 using the unnatural amino acid derived fragment 4-amino-1,2-dithiolane-4-carboxamide 2.80. In a second project, a library of substituted 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles and 9Hpyrido[3,4-b]indoles was successfully synthesised based on a target-based directed study. Using a Pictet-Spengler reaction enabled access to the desired compounds. Furthermore, molecular modelling and biological evaluation studies were carried out to determine if the prepared compounds were inhibitors of the enzyme PC-PLC and therefore potential inhibitors for the development of some cancers of which this enzyme is involved in their cell signalling pathways.