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Pharmaceuticals 2017, 10(3), 62; doi:10.3390/ph10030062

Synthesis and Antiproliferative Activity of Novel Heterocyclic Indole-Trimethoxyphenyl Conjugates

School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Western Road, Cork T12 YN60, Ireland
Author to whom correspondence should be addressed.
Academic Editor: Jean Jacques Vanden Eynde
Received: 26 May 2017 / Revised: 26 June 2017 / Accepted: 27 June 2017 / Published: 5 July 2017
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The synthesis and biological evaluation of a series of novel heterocyclic indole derivatives is described. The consolidation of the combretastatin and bisindolylmaleimide templates towards the inclusion of a novel heterocyclic ring proffered a versatile pharmacophore with which to pursue chemical diversification. Given literature precedent, maleimide was initially investigated in this role and the bioactivity assessed by measurement of NCI-60 cell panel growth. Subsequently, a range of 5-aminopyrazoles was designed and developed to explore the specific effect of heterocycle hydrogen bonding on cell growth. The unique electronic nature of the 5-aminopyrazole moiety allowed for regiospecific monosubstitution on different sites of the ring, such as thiourea substitution at the N(1) position for derivative 45 or trifluoroacetylation on the 5-amino position for 43. Further derivatisation led to the ultimate development of bicyclic pyrazolotriazinedione 41 and pyrimidine 42 systems. The antiproliferative activities of these 3,4-diaryl-5-aminopyrazoles were assessed using the NCI-60 cell screen, disclosing the discovery of distinct selectivity profiles towards a number of cell lines, such as SNB-75 CNS cancer, UO-31 and CAKI-1 renal cancer cells. A series of DNA topological assays discounted the interaction with topoisomerase II as a putative mechanism of action. View Full-Text
Keywords: diarylmaleimide; diaryl-aminopyrazole; 5-aminopyrazole regioselective substitution; drug discovery; NCI anticancer screen diarylmaleimide; diaryl-aminopyrazole; 5-aminopyrazole regioselective substitution; drug discovery; NCI anticancer screen

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Cahill, M.M.; O’Shea, K.D.; Pierce, L.T.; Winfield, H.J.; Eccles, K.S.; Lawrence, S.E.; McCarthy, F.O. Synthesis and Antiproliferative Activity of Novel Heterocyclic Indole-Trimethoxyphenyl Conjugates. Pharmaceuticals 2017, 10, 62.

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