Imidazopyridine-fused [1,3]diazepinones: modulations of positions 2 to 4 and their impacts on the anti-melanoma activity

Paul Le Baccon-Sollier,Yohan Malki,Morgane Maye,Lamiaa M A Ali,Laure Lichon,Pierre Cuq,Laure-Anaïs Vincent,Nicolas Masurier

doi:10.1080/14756366.2020.1748024

Abstract

A series of 19 novel pyrido-imidazodiazepinones, with modulations of positions 2, 3 and 4 of the diazepine ring were synthesised and screened for their in vitro cytotoxic activities against two melanoma cell lines (A375 and MDA-MB-435) and for their potential toxicity against NIH-3T3 non-cancerous cells. Selected compounds were also evaluated on the NCI-60 cell line panel. The SAR study revealed that the molecular volume and the cLogP of compounds modified at position 2 were significantly correlated with the activity of these compounds on melanoma cell lines. Moreover, introduction of a heterocyclic group at position 2 or an azido-alkyl chain at position 4 led to compounds displaying a significantly different activity profile on the NCI-60 cell line panel, compared to phenyl-substituted compounds at position 2 of the diazepinone. This study provides us crucial information for the development of new derivatives active against melanoma.

Highlights

Melanoma is the most aggressive skin cancer and remains a therapeutic challenge
Introduction of a 4-ethynyl, a 4-azidophenyl substituent was tolerated onto the position 2 of the diazepine ring and led to compounds with a similar in vitro activity on melanoma cells and with no apparent toxicity on NIH-3T3 cells
Introduction of a bicyclic and heteroaromatic group on this position led to compounds possessing a significant difference of activity towards the two tested melanoma cell lines

Summary

Introduction

Melanoma is the most aggressive skin cancer and remains a therapeutic challenge. Since 2011, new therapeutic strategies have emerged and offer promising results. The rapid emergence of drug resistance to initially responsive cancers has led to only marginal patient benefit. To limit these resistances, mainly due to the reactivation of the MAPK pathway, MEK inhibitors (Trametinib, Cobimetinib, Binimetinib) are used in combination. Association between targeted therapies and immunotherapies confers a longer progression-free survival and duration of response, but led to a higher rate of serious toxicity. The development of new drugs that could be used in combination with mentioned therapies is still in demand to overcome the extreme chemoresistance of metastatic melanoma

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Conclusion