2. Academic Validation
  3. Synthesis and growth-inhibitory activities of imidazo[5,1- d]-1,2,3,5-tetrazine-8-carboxamides related to the anti-tumour drug temozolomide, with appended silicon, benzyl and heteromethyl groups at the 3-position

Synthesis and growth-inhibitory activities of imidazo[5,1- d]-1,2,3,5-tetrazine-8-carboxamides related to the anti-tumour drug temozolomide, with appended silicon, benzyl and heteromethyl groups at the 3-position

  • Medchemcomm. 2018 Jan 19;9(3):545-553. doi: 10.1039/c7md00554g.
David Cousin 1,  Marc G Hummersone 1,  Tracey D Bradshaw 2,  Jihong Zhang 2,  Christopher J Moody 3,  Magdalena B Foreiter 3,  Helen S Summers 3,  William Lewis 3,  Richard T Wheelhouse 4,  Malcolm F G Stevens 2
Affiliations

Affiliations

  • 1 Pharminox Ltd , Biocity , Pennyfoot St. , Nottingham NG1 1GF , UK.
  • 2 School of Pharmacy , University of Nottingham , NG7 2RD , UK . Email: tracey.bradshaw@nottingham.ac.uk ; Email: malcolm.stevens@nottingham.ac.uk.
  • 3 School of Chemistry , University of Nottingham , NG7 2RD , UK . Email: c.j.moody@nottingham.ac.uk.
  • 4 Institute of Cancer Therapeutics , School of Pharmacy and Medical Sciences , University of Bradford , Bradford , BD7 1DP , UK.
PMID: 30108945 DOI: 10.1039/c7md00554g
Abstract

A series of 3-(benzyl-substituted)-imidazo[5,1-d]-1,2,3,5-tetrazines (13) and related derivatives with 3-heteromethyl groups has been synthesised and screened for growth-inhibitory activity in vitro against two pairs of glioma cell lines with temozolomide-sensitive and -resistant phenotypes dependent on the absence/presence of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In general the compounds had low inhibitory activity with GI50 values >50 μM against both sets of cell lines. Two silicon-containing derivatives, the TMS-methylimidazotetrazine (9) and the SEM-analogue (10), showed interesting differences: compound (9) had a profile very similar to that of temozolomide with the MGMT+ cell lines being 5 to 10-fold more resistant than MGMT- isogenic partners; the SEM-substituted compound (10) showed potency across all cell lines irrespective of their MGMT status.

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