Synthesis and antiproliferative activity of novel heterocyclic indole-trimethoxyphenyl conjugates
Extracted File 1
Cahill, Michael M.
O'Shea, Kevin D.
Eccles, Kevin S.
Lawrence, Simon E.
McCarthy, Florence O.
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
Diarylmaleimide , Diaryl-aminopyrazole , 5-aminopyrazole regioselective substitution , Drug discovery , NCI anticancer screen
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