Synthesis of novel heterocyclic compounds that enhance the anticancer effects of Saha

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Copyright: Bingul, Murat
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Abstract
The tricyclic indole and tetracyclic quinoline heterocyclic systems were chosen from Naresh Kumar (NK) library in terms of their structural similarity to compounds identified from WEHI library screening. It was also of a particular interest to modify the structure of WEHI 0088846 and test the new analogues against the designated cancer cells. A suitable methodology was developed for the preparation of novel dihydropyranoindoles via the Hemetsberger indole synthesis of arylethers, derived from corresponding hydroxybenzaldehydes with activated alkynes, and a thermal cyclisation in high boiling solvents. Biological studies showed that tetracyclic systems had significant cytotoxic activity at higher concentration against the neuroblastoma cancer cells. More importantly, these systems, at the lower concentration, considerably enhanced the SAHA toxicity. Encouragingly, the toxicity of designated systems on the normal human cells was found to be significantly less than the cancer cells. The nucleophilic substitution of methyl hydroxyindole esters with α-haloketones yielded the arylether ketones and subsequent cyclisation resulted in tricyclic and tetracyclic furoindoles. The attempts to cyclize the corresponding intermediates in the presence of catalytic amount of acid generated the desired tricyclic and tetracyclic furoindoles. The additional mono cyclized furoindoles with the non-cyclized methyl ketone were arised from methyl 4,6-dihydroxyindole-2-carboxylate. The individual cytotoxic efficency of furoindoles were found to be more favourable than the SAHA enhancement effect against the cancer cells. Interestingly, the non-cyclized intermediate provided the best IC50 value at very low concentration. The first synthetic procedure to prepare the original hit compound WEHI 0088846 was reported and the modifications on the three key regions of compound afforded a range of analogues in good yields. The new hydrazone-hydrazide compounds were found to be cell specific towards the neuroblastoma cells and two derivatives displayed very low micromolar potency against the neuroblastoma cells. The most reactive position of the methyl 5,6-dibenzyloxyindole esters was determined via the Vilsmeier Haack reaction and formylated products were used for the design of novel indole-containing imines. The tested imine analogues were shown to have a significant potential for the reduction of Kelly cell viability at a concentration of 10 μM compound alone.
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Author(s)
Bingul, Murat
Supervisor(s)
Black, David StC
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Publication Year
2014
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Thesis
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PhD Doctorate
UNSW Faculty
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