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

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.

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

“…Briefly, while positions 3 and 5 could be modified without losing activity, various aromatic nuclei could be introduced in position 2 of the ring. In this case a correlation was found between the cytotoxic activity of the compound, its logP and the molecular volume of the introduced substituent 288 . Regarding position 4, the S stereochemistry was crucial for the activity and short linear alkyl chains were tolerated.…”

“…The most active compounds were also tested on the healthy fibroblast NIH3T3 cell line. They did not show any significant toxicity on this cell line, even at high concentration (100 µM), suggesting a good selectivity of these compounds for cancer cells 287,288 . Additional studies showed that JMV5038 and some of these analogues induced an increase in the proportion of cells in the G2/M phase, and an appearance of cells in the subG1 phase 288 .…”

“…While a first screening realized on the NCI‐60 cell line panel, a compound called JMV5038 showed the most potent activities 287 . IC 50 in the micromolar range were obtained against several cell lines, including MDA‐MB‐435 and A375 melanoma cell lines (IC 50 = 1.3 µM and 2.1 µM, respectively) 288 . Modulations at positions 2, 3, 4, and 5 of the 1,3‐diazepine ring were studied, 286,288 and the main results are shown in Figure 35C.…”

“…IC 50 in the micromolar range were obtained against several cell lines, including MDA‐MB‐435 and A375 melanoma cell lines (IC 50 = 1.3 µM and 2.1 µM, respectively) 288 . Modulations at positions 2, 3, 4, and 5 of the 1,3‐diazepine ring were studied, 286,288 and the main results are shown in Figure 35C. Briefly, while positions 3 and 5 could be modified without losing activity, various aromatic nuclei could be introduced in position 2 of the ring.…”

PROteolysis TArgetting Chimeras (PROTACs) Strategy Applied to Kinases: Recent Advances

“…Although much progress has been made to increase patient responses (use of immunotherapies and/or drugs combination), development of new compounds or strategies to limit the occurrence of resistance in melanoma cell lines is still in demand. [ 137–139 ]…”