Synthesis and Antiproliferative Activity of Novel Heterocyclic Indole-Trimethoxyphenyl Conjugates
AbstractThe 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
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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.
Cahill MM, O’Shea KD, Pierce LT, Winfield HJ, Eccles KS, Lawrence SE, McCarthy FO. Synthesis and Antiproliferative Activity of Novel Heterocyclic Indole-Trimethoxyphenyl Conjugates. Pharmaceuticals. 2017; 10(3):62.Chicago/Turabian Style
Cahill, Michael M.; O’Shea, Kevin D.; Pierce, Larry T.; Winfield, Hannah J.; Eccles, Kevin S.; Lawrence, Simon E.; McCarthy, Florence O. 2017. "Synthesis and Antiproliferative Activity of Novel Heterocyclic Indole-Trimethoxyphenyl Conjugates." Pharmaceuticals 10, no. 3: 62.
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