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Enhancing the anti-lymphoma potential of 3,4-methylenedioxymethamphetamine (‘ecstasy’) through iterative chemical redesign: mechanisms and pathways to cell death

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Summary

While 3,4-methylenedioxymethamphetamine (MDMA/‘ecstasy’) is cytostatic towards lymphoma cells in vitro, the concentrations required militate against its translation directly to a therapeutic in vivo. The possibility of ‘redesigning the designer drug’, separating desired anti-lymphoma activity from unwanted psychoactivity and neurotoxicity, was therefore mooted. From an initial analysis of MDMA analogues synthesized with a modified α-substituent, it was found that incorporating a phenyl group increased potency against sensitive, Bcl-2-deplete, Burkitt’s lymphoma (BL) cells 10-fold relative to MDMA. From this lead, related analogs were synthesized with the ‘best’ compounds (containing 1- and 2-naphthyl and para-biphenyl substituents) some 100-fold more potent than MDMA versus the BL target. When assessed against derived lines from a diversity of B-cell tumors MDMA analogues were seen to impact the broad spectrum of malignancy. Expressing a BCL2 transgene in BL cells afforded only scant protection against the analogues and across the malignancies no significant correlation between constitutive Bcl-2 levels and sensitivity to compounds was observed. Bcl-2-deplete cells displayed hallmarks of apoptotic death in response to the analogues while BCL2 overexpressing equivalents died in a caspase-3-independent manner. Despite lymphoma cells expressing monoamine transporters, their pharmacological blockade failed to reverse the anti-lymphoma actions of the analogues studied. Neither did reactive oxygen species account for ensuing cell death. Enhanced cytotoxic performance did however track with predicted lipophilicity amongst the designed compounds. In conclusion, MDMA analogues have been discovered with enhanced cytotoxic efficacy against lymphoma subtypes amongst which high-level Bcl-2—often a barrier to drug performance for this indication—fails to protect.

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Abbreviations

ABC:

Activated B-Cell-like

BL:

Burkitt’s lymphoma

DAT:

Dopamine transporter

DLBCL:

Diffuse large B-cell lymphoma

EBV:

Epstein-Barr virus

FL:

Follicular lymphoma

GCB:

Germinal B-Cell-like

MDMA:

3,4-methylenedioxymethamphetamine

NHL:

Non-Hodgkin lymphomas

PARP:

Poly (ADP-ribose) polymerase

PI:

Propidium iodide

PTLD:

Post-transplant lymphoproliferative disease

SERT:

Serotonin transporter

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Acknowledgements

This work was supported in part by Leukaemia and Lymphoma Research, UK, and the Ada Bartholomew Medical Research Trust, W.A. MNG and KDL were recipients of a UWA postgraduate scholarship and Australian Postgraduate Award, respectively. DS-T was supported by an Arthritis Research UK Career Progression Fellowship. JG was in receipt of a Raine Visiting Professorship at the University of Western Australia while writing the paper. The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. School of Immunity & Infection, The Medical School, Birmingham, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Agata M. Wasik, Michelle J. Holder, Anita Chamba, Anita Challa, Stephen P. Young, Dagmar Scheel-Toellner & John Gordon

  2. School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Crawley, Australia

    Michael N. Gandy, Matthew McIldowie, Katie D. Lewis & Matthew J. Piggott

  3. Medical Research Council Toxicology Unit, Leicester, UK

    Martin J. Dyer

  4. Cellular and Molecular Neuropharmacology Research Group, Clinical and Experimental Medicine, The Medical School, Birmingham, UK

    Nicholas M. Barnes

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Correspondence to John Gordon.

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Matthew J. Piggott, Nicholas M. Barnes, and John Gordon are joint senior authors

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Wasik, A.M., Gandy, M.N., McIldowie, M. et al. Enhancing the anti-lymphoma potential of 3,4-methylenedioxymethamphetamine (‘ecstasy’) through iterative chemical redesign: mechanisms and pathways to cell death. Invest New Drugs 30, 1471–1483 (2012). https://doi.org/10.1007/s10637-011-9730-5

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