Synthesis and Biological Evaluation of Novel Analogues of the Plant Derived Natural Products, Incarviditone and Incarvilleatone

UoM administered thesis: Master of Science by Research

  • Authors:
  • Nur Izzati Abdul Ghaffar

Abstract

Incarviditone is a perhydrobenzofuranone dimer isolated from Incarvillea delavayi in 2009. Past work from the Whitehead research group involved the syntheses and biological evaluations of incarviditone analogues. The purpose of this research was to expand the library of incarviditone analogues in order to discover a lead compound with an enhanced biological profile. This was achieved by synthesising and performing biological assays on two novel analogues: 4-butylphenyl and benzo[b]thien-3yl substituents. A known, consistently potent analogue (4-tert-butylphenyl) was also resynthesised for further biological evaluations. The synthesis of 4-butylphenyl and 4-tert-butylphenyl substituents were successfully achieved following a linear sequence of synthetic pathway developed by the Whitehead group. The yields obtained were moderate for both dimers: 56% and 52% respectively. The synthesis of the benzo[b]thien-3yl substituent was challenging due to rapid decomposition in the 1,4-addition. This was overcome with the employment of organotrifluoroborate salt and hydroxy Rh(I) catalyst; albeit low yield was obtained for the conjugate adduct (16%). The dimerisation for the benzo[b]thien-3yl substituent proceeded with a decent yield of 34%. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and sulforhodamine B (SRB) assays were conducted on the 4-butylphenyl and 4-tert-butylphenyl dimers and their hydroxyenone intermediates against A549 (lung) and MDA-MB-231 (breast) cancer cell lines. The biological results showed that both dimers were cytotoxic against the two cell lines, with the 4-tert-butylphenyl dimer being slightly more potent than the 4-butylphenyl dimer. The biological assays could not be performed on the benzo[b]thien-3yl dimer due to time constraints of a one-year Masters by Research.

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Original languageEnglish
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Award date1 Aug 2020