XIAP as a Target of New Small Organic Natural Molecules Inducing Human Cancer Cell Death.

Muñoz Muñoz,Lopez-Vallejo Lopez-Vallejo,Zecchini Zecchini,Catalani Catalani,Perrotta Perrotta,Coazzoli Coazzoli,Arboleda Arboleda,De Palma De Palma,Delgado Delgado,Clementi Clementi,Cervia Cervia,Giovarelli Giovarelli,Cuca Cuca,Brucoli Brucoli,Sandoval-Hernandez Sandoval-Hernandez

doi:10.3390/cancers11091336

Abstract

X-linked inhibitor of apoptosis protein (XIAP) is an emerging crucial therapeutic target in cancer. We report on the discovery and characterisation of small organic molecules from Piper genus plants exhibiting XIAP antagonism, namely erioquinol, a quinol substituted in the 4-position with an alkenyl group and the alkenylphenols eriopodols A–C. Another isolated compound was originally identified as gibbilimbol B. Erioquinol was the most potent inhibitor of human cancer cell viability when compared with gibbilimbol B and eriopodol A was listed as intermediate. Gibbilimbol B and eriopodol A induced apoptosis through mitochondrial permeabilisation and caspase activation while erioquinol acted on cell fate via caspase-independent/non-apoptotic mechanisms, likely involving mitochondrial dysfunctions and aberrant generation of reactive oxygen species. In silico modelling and molecular approaches suggested that all molecules inhibit XIAP by binding to XIAP-baculoviral IAP repeat domain. This demonstrates a novel aspect of XIAP as a key determinant of tumour control, at the molecular crossroad of caspase-dependent/independent cell death pathway and indicates molecular aspects to develop tumour-effective XIAP antagonists.

Highlights

The characterisation of small molecules with well-defined chemical structures is a good approach to develop new therapeutic agents in proliferative, Cancers 2019, 11, 1336; doi:10.3390/cancers11091336 www.mdpi.com/journal/cancersCancers 2019, 11, 1336 infectious, or neurodegenerative disorders [1–5]
The chemical structures of compounds isolated from leaves of P. eriopodon (Figure 1A) were identified by interpretation of their corresponding high resolution electrospray ionisation mass spectrometry (HRESIMS), 1H- and 13C-NMR spectral data, including attached proton test (APT), correlated spectroscopy (COSY), heteronuclear multiple quantum coherence (HMQC) and heteronuclear multiple bond correlation (HMBC) experiments, as well as by comparison of the spectral data with those reported in the literature
Based on the 13C-NMR chemical shifts of the allylic carbons δC 34.6 (C-2’) and δC 32.6 (C-5’), the configuration of the double bond for compound 2 was assigned as E [18], by comparison with the 13C-NMR chemical shift of the allylic carbons in the E analogue gibbilimbol B (δC 34.6 (C-2’) and δC 32.6 (C-5’)), which differed significantly from the chemical shift values reported for the Z analogue climacostol [δC 33.2 (C-1’) Canacnerds 2δ0C192,71.13, (1C33-64’)] [44]

Summary

Introduction

The characterisation of small molecules (whose molecular weight does not exceed 900 Daltons) with well-defined chemical structures is a good approach to develop new therapeutic agents in proliferative, Cancers 2019, 11, 1336; doi:10.3390/cancers11091336 www.mdpi.com/journal/cancersCancers 2019, 11, 1336 infectious, or neurodegenerative disorders [1–5]. Natural products possess enormous structural and chemical diversity that cannot be matched by any synthetic libraries of small molecules and continue to show a great translational potential [6–10]. The complex chemical composition of some natural products has made difficult their isolation, structure elucidation and characterisation, prompting the search of new efficient synthetic pathways. The simple active chemical structures of phenolic compounds from plants make them optimal lead candidates because of their broad biological activity, especially the protective, anti-oxidant and anti-tumour effects [11–14]. Piper genus constitutes one major class of medicinal plants and contains a valuable resource of phenolic bioactive compounds [15–21]. Piplartine, hydroxychavicol, 4-nerodlidylcatechol and gibbilimbols A–D displayed potent cytotoxic/anti-tumoural effects in a variety of human cancer cells in vitro and in vivo [19,22–29]

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Conclusion