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Enhancing the anti-lymphoma potential of 3,4-methylenedioxymethamphetamine ('ecstasy') through iterative chemical redesign: mechanisms and pathways to cell death.
Invest New Drugs 2012; 30(4):1471-83IN

Abstract

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.

Authors+Show Affiliations

School of Immunity & Infection, The Medical School, Birmingham, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21850491

Citation

Wasik, Agata M., et al. "Enhancing the Anti-lymphoma Potential of 3,4-methylenedioxymethamphetamine ('ecstasy') Through Iterative Chemical Redesign: Mechanisms and Pathways to Cell Death." Investigational New Drugs, vol. 30, no. 4, 2012, pp. 1471-83.
Wasik AM, Gandy MN, 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. 2012;30(4):1471-83.
Wasik, A. M., Gandy, M. N., McIldowie, M., Holder, M. J., Chamba, A., Challa, A., ... Gordon, J. (2012). Enhancing the anti-lymphoma potential of 3,4-methylenedioxymethamphetamine ('ecstasy') through iterative chemical redesign: mechanisms and pathways to cell death. Investigational New Drugs, 30(4), pp. 1471-83. doi:10.1007/s10637-011-9730-5.
Wasik AM, 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. 2012;30(4):1471-83. PubMed PMID: 21850491.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhancing the anti-lymphoma potential of 3,4-methylenedioxymethamphetamine ('ecstasy') through iterative chemical redesign: mechanisms and pathways to cell death. AU - Wasik,Agata M, AU - Gandy,Michael N, AU - McIldowie,Matthew, AU - Holder,Michelle J, AU - Chamba,Anita, AU - Challa,Anita, AU - Lewis,Katie D, AU - Young,Stephen P, AU - Scheel-Toellner,Dagmar, AU - Dyer,Martin J, AU - Barnes,Nicholas M, AU - Piggott,Matthew J, AU - Gordon,John, Y1 - 2011/08/18/ PY - 2011/06/08/received PY - 2011/08/01/accepted PY - 2011/8/19/entrez PY - 2011/8/19/pubmed PY - 2012/10/30/medline SP - 1471 EP - 83 JF - Investigational new drugs JO - Invest New Drugs VL - 30 IS - 4 N2 - 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. SN - 1573-0646 UR - https://www.unboundmedicine.com/medline/citation/21850491/abstract/Enhancing_the_anti_lymphoma_potential_of_34_methylenedioxymethamphetamine__'ecstasy'__through_iterative_chemical_redesign:_mechanisms_and_pathways_to_cell_death_ L2 - https://doi.org/10.1007/s10637-011-9730-5 DB - PRIME DP - Unbound Medicine ER -