Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/22813
Title: Affinity-guided Isolation, Structure Elucidation and Total Synthesis of Laetirobin A and Its Analogue Synthesis for Therapeutic Development
Authors: OLIVER SIMON
Keywords: antitumor agent, affinity guided isolation, biomimetic synthesis, cycloaddition, total synthesis
Issue Date: 18-Jan-2011
Source: OLIVER SIMON (2011-01-18). Affinity-guided Isolation, Structure Elucidation and Total Synthesis of Laetirobin A and Its Analogue Synthesis for Therapeutic Development. ScholarBank@NUS Repository.
Abstract: (?)-Laetirobin A was isolated as a cytostatic lead from Laetiporus sulphureus growing parasitically on the black locust tree, Robinia pseudoacacia, by virtue of a reverse-immunoaffinity system. The structure of the secondary metabolite was elucidated by X-ray crystallography and confirmed by NMR spectroscopy. Intrigued by its pseudo-symmetrical nature, a total synthesis based on a dual functionalisation approach was conducted. Highlights of this approach include the double-Sonogashira reaction of a bis(alkyne)carbinol, the practical copper(I)-catalysed modified Castro-Stevens cyclisation of a bis(benzo[b]-furan), and the biomimetic [4+2] dimerisation ((?)-laetirobin A) and the unexpected cationic [5+2] annulations (Iso-laetirobin) of gem-diaryl alkene precursors. This highly efficient approach afforded (?)-laetirobin A in six scalable steps and in 14% overall yield. Preliminary cellular studies indicated that (?)-laetirobin A rapidly enters in tumor cells, blocks cell division at a late stage of mitosis, and invokes apoptosis. The unnatural [5+2]-dimerisation product, named iso-laetirobin, does not display any significant effects on tested cancer cell lines. Encouraged by the desirable attributes for an anti-cancer agent as displayed by (?)-laetirobin A, synthetic efforts towards analogues for therapeutic development were made. The first round of structure-activity relationship studies (SAR) was focused on the importance of substituents and the pharmacophore elucidation of (?)-laetirobin A. The [4+2]- and the [5+2]-cyclodimerisation products of the unsubstituted analogues were obtained. The developed dual functionalisation approach also afforded the analogue lacking the hydroxyl substituents. The analogue lacking the acetyl groups was found unstable and underwent immediate autoxidation processes. Work on the pharmacophore elucidation is still on-going. Further synthetic efforts towards the total synthesis of the putative biosynthetic precursor, laetirobin B, were also initiated. The aim of these efforts was to eventually prove the postulated biosynthesis, namely, a spontaneous [4+2]-cyclodimerisation in a non-enzymatic environment of (?)-laetirobin A. This part of the work has yet to be completed, although unexpected but interesting results have been found and are described herein.
URI: http://scholarbank.nus.edu.sg/handle/10635/22813
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