Antimelanoma activities of chimeric thiazole-androstenone derivatives.

Steven A Chambers,Alena V Savenka,Alexei G Basnakian,Mathew Newman,Mohammad A Alam,Melissa M Frangie

doi:10.1098/rsos.210395

Abstract

The discovery of chimeric anti-melanoma agents is reported. These molecules are potent growth suppressors of melanoma cells in vitro with growth inhibition of 50% (GI50) values as low as 1.32 µM. Compounds were more toxic to melanoma cells in vitro than commonly used anti-melanoma agent dacarbazine as measured by TUNEL assay. They induced both caspase-independent apoptosis evident by colocalization of TUNEL with endonuclease G (EndoG) and caspase-mediated apoptosis measured by colocalization of TUNEL with caspase-activated DNase (CAD). In addition, compounds 3 and 5 strongly induced oxidative injury to melanoma cells as measured by TUNEL colocalization with heme oxygenase-1 (HO1). Dacarbazine induced only caspase-independent apoptosis, which may explain why it is less cytotoxic to melanoma cells than compounds 3, 4 and 5.

Highlights

The discovery of chimeric anti-melanoma agents is reported
Compounds were more toxic to melanoma cells in vitro than commonly used anti-melanoma agent dacarbazine as measured by transferase dUTP nick-end labelling (TUNEL) assay. They induced both caspaseindependent apoptosis evident by colocalization of TUNEL with endonuclease G (EndoG) and caspase-mediated apoptosis measured by colocalization of TUNEL with caspase-activated DNase (CAD)
Some of the approved drugs are dasatinib to treat Philadelphia chromosome-positive chronic myelogenous leukaemia (CML) and acute lymphoblastic leukaemia (ALL), dabrafenib to treat BRAF-positive cancers and ixabepilone aimed at breast cancer [6,7]

Summary

Introduction

The discovery of chimeric anti-melanoma agents is reported. These molecules are potent growth suppressors of melanoma cells in vitro with growth inhibition of 50% (GI50) values as low as 1.32 μM. Dacarbazine induced only caspase-independent apoptosis, which may explain why it is less cytotoxic to melanoma cells than compounds 3, 4 and 5. Phenyl substituted derivative (2) showed good activity against LOX IMVI and MDA-MB-435 cell lines with GI50 values of 3.22 and 3.49 μM, respectively.

Results

Conclusion