Synthesis and Characterisation of Novel Tricyclic and Tetracyclic Furoindoles: Biological Evaluation as SAHA Enhancer against Neuroblastoma and Breast Cancer Cells.

Murat Bingul,Glenn M Marshall,Belamy B Cheung,Greg M Arndt,David Stc Black,Naresh Kumar

doi:10.3390/molecules26195745

Murat Bingul, Glenn M Marshall + Show 4 more

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https://doi.org/10.3390/molecules26195745

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Abstract

The dihydropyranoindole structures were previously identified as promising scaffolds for improving the anti-cancer activity of histone deacetylase inhibitors. This work describes the synthesis of related furoindoles and their ability to synergize with suberoylanilide hydroxamic acid (SAHA) against neuroblastoma and breast cancer cells. The nucleophilic substitution of hydroxyindole methyl esters with α-haloketones yielded the corresponding arylether ketones, which were subsequently cyclized to tricyclic and tetracyclic furoindoles. The furoindoles showed promising individual cytotoxic efficiency against breast cancer cells, as well as decent SAHA enhancement against cancer cells in select cases. Interestingly, the best IC50 value was obtained with the non-cyclized intermediate.

Highlights

Suberoylanilide hydroxamic acid (SAHA, known as vorinostat) is an anticancer therapeutic agent due to its histone deacetylase (HDAC) inhibitory activity [1,2,3]
Cell lines were treated with 1 μM suberoylanilide hydroxamic acid (SAHA) (SH-SY5Y) and 0.5 μM SAHA (Kelly), 10 μM of the compounds, or their combination over 72 h, and cell viabilities were normalized to a DMSO control
The greatest SAHA enhancement was achieved by compound 43, where the combination decreased SH-SY5Y cell viability (41%) by a further 29% compared to SAHA alone (70%)

Summary

Introduction

Suberoylanilide hydroxamic acid (SAHA, known as vorinostat) is an anticancer therapeutic agent due to its histone deacetylase (HDAC) inhibitory activity [1,2,3]. The inhibition of HDAC enzymes results in the accumulation of acetylated histones, which in turn leads to an increase in transcriptionally active chromatin [4,5]. As SAHA targets only one signalling pathway or molecular mechanism, single-agent treatment with SAHA was ineffective against several cancers [9,10]. The combination of SAHA with other chemotherapeutic agents with different mechanisms of action has been considered to be a promising approach to overcome resistance to single-agent therapies [9,10,11]

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