Synthesis and antiproliferative activity of novel heterocyclic indole-trimethoxyphenyl conjugates
| Autor: | Larry T. Pierce, Florence O. McCarthy, Simon E. Lawrence, Kevin O'Shea, Kevin S. Eccles, Michael M. Cahill, Hannah J. Winfield |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Pyrimidine
Stereochemistry Pharmaceutical Science lcsh:Medicine lcsh:RS1-441 Diarylmaleimide 01 natural sciences Article drug discovery lcsh:Pharmacy and materia medica 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Moiety diarylmaleimide Maleimide diaryl-aminopyrazole 5-aminopyrazole regioselective substitution NCI anticancer screen Indole test Combretastatin Bicyclic molecule 010405 organic chemistry Chemistry Cell growth Drug discovery lcsh:R Diaryl-aminopyrazole 0104 chemical sciences 030220 oncology & carcinogenesis Molecular Medicine Pharmacophore |
| Zdroj: | Pharmaceuticals Pharmaceuticals; Volume 10; Issue 3; Pages: 62 Pharmaceuticals, Vol 10, Iss 3, p 62 (2017) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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