Cover Feature: Synthesis of Bioactive Side‐Chain Analogues of TAN‐2483B (Chem. Asian J. 8/2019)

Abstract

Side‐chain analogues of the natural product TAN‐2483B have been synthesised and tested for cancer cell and kinase inhibition. The furo[3,4‐b]pyran scaffold was constructed through ring expansion of a mannose‐derived cyclopropane, alkynylation and carbonylative lactonisation. Various side chains were appended using Wittig methodology. The cover picture illustrates key intermediates in the synthesis leading to the prepared analogues. These are overlaid on a New Zealand native fern, signifying the origin of the research presented in this special issue on Chemistry in New Zealand. More information can be found in the Full Paper by Joanne Harvey et al. on page 1230 in Issue 8, 2019 (DOI: 10.1002/asia.201801767).

A Structure‐Activity Investigation of the Fungal Metabolite (−)‐TAN‐2483B: Inhibition of Bruton's Tyrosine Kinase

“…We extend the utility of our previously established synthetic route [5],[6] to access new analogues featuring modifications of functional groups which were deemed important in the modelling predictions. Their inhibitory activity along with three previously reported sidechain variants [5] are determined, which altogether map a clear structure‐activity relationship (SAR) between the furopyranone ring system and Btk, and corroborate modelling predictions. New analogues were discovered which displayed enhanced potency for Btk relative to the natural product, as well as activity against other cancer and immune‐relevant kinases.…”

“…Interestingly, the ( E )‐enoate sidechain readily underwent conjugate reduction, whereas the ( Z )‐enoate was unreactive and instead the skipped enyne isomerised into conjugation, which we had previously observed with related intermediates [6] . Nevertheless, the successful reduction of the ( E )‐isomer indicated its suitability for the synthetic approach and, as ( E )‐ 10 was able to be selectively generated [5] . Subjection of the ( E )‐isomer alone to the reduction conditions gave the desired product in exceptional purity with no evidence of enyne isomerisation.…”

“…The synthetic strategy for saturated sidechain analogue 6 utilises an advanced intermediate ( 10 ), accessible through our previously reported carbohydrate‐based route [5] . A conjugate reduction of the α,β‐unsaturated ester within species ( E )‐ 10 [5] (Figure 1B) was attempted by modulating the activity of NaBH 4 with CuCl [10] . During initial attempts, mixtures of both geometric isomers of 10 were used to trial the reaction conditions.…”

“…As part of our continuing investigation into the chemistry and bioactivity of natural products and analogues thereof, [4–10] we have been investigating the furo[3,4‐ b ]pyran‐5‐one ring system present in several fungal natural products, including (−)‐TAN‐2483B ( 1 ), as a platform for exploring synthetic methodology and for uncovering new bioactive compounds. (−)‐TAN‐2483B is a secondary metabolite of fungal origin [11] belonging to a small and under‐explored family of compounds which show intriguing anti‐cancer and immunomodulatory properties.…”

“…Our recent synthesis and biological assessment of (−)‐TAN‐2483B ( 1 ) [6] and sidechain analogues 2–5 [5] (Figure 1) uncovered selective inhibition of Bruton's tyrosine kinase (Btk), a TEC‐family kinase which plays an important role in haematopoiesis by mediation of the B lymphocyte signalling pathways [16] . Btk is a clinical drug target for treating leukaemia and immune‐related diseases, with four FDA‐approved inhibitors on the market, including: ibrutinib, [17] acalabrutinib, [18] zanubrutinib, [19] and pirtobrutinib [20] (Figure S1), and several more undergoing clinical assessment [21] .…”