Synthesis and antiproliferative activity of novel heterocyclic indole-trimethoxyphenyl conjugates
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Date
2017
Authors
Cahill, Michael M.
O'Shea, Kevin D.
Pierce, Larry
Winfield, Hannah
Eccles, Kevin S.
Lawrence, Simon E.
McCarthy, Florence O.
Journal Title
Journal ISSN
Volume Title
Publisher
MDPI
Published Version
Abstract
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
Description
Keywords
Diarylmaleimide , Diaryl-aminopyrazole , 5-aminopyrazole regioselective substitution , Drug discovery , NCI anticancer screen
Citation
Cahill, M., O’Shea, K., Pierce, L., Winfield, H., Eccles, K., Lawrence, S. and McCarthy, F. (2017) 'Synthesis and antiproliferative activity of novel heterocyclic indole-trimethoxyphenyl conjugates', Pharmaceuticals, 10(3), 62 (20pp). doi: 10.3390/ph10030062