Redesigning the designer drug ecstasy: non-psychoactive MDMA analogues exhibiting Burkitt's lymphoma cytotoxicity

Abstract

Burkitt's lymphoma (BL) is a particularly aggressive cancer that primarily affects African children. Unfortunately, effective and affordable treatment is out of reach of most of the afflicted. The illicit psychoactive drug methylenedioxymethamphetamine (MDMA, 'ecstasy') is cytotoxic to BL cell lines, but its low potency, psychoactivity and neurotoxicity preclude consideration as a therapeutic drug candidate. This paper describes the discovery of novel a-aryl analogues of MDMA that lack psychoactivity and reduce BL cell line viability with significantly more potency than the lead compound. Preliminary in vitro studies also indicate that the compounds are non-toxic to a relevant neuronal cell line.

Characterization of 3,4-Methylenedioxymethamphetamine (MDMA) EnantiomersIn Vitroand in the MPTP-Lesioned Primate:R-MDMA Reduces Severity of Dyskinesia, WhereasS-MDMA Extends Duration of ON-Time

“…The receptor and transporter binding assays performed in the current study targeted only the receptor/ transporters to which racemic MDMA was shown to display affinity in a previous experiment performed by our group (Gandy et al, 2010). Even though MDMA did not display high affinity at 5-HT 1A receptors in that experiment, we have nevertheless performed 5-HT 1A receptor binding for both enantiomers, as it has been suggested that MDMA's antidyskinetic effect involved a 5-HT 1A -mediated mechanism .…”

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

“…A companion study shows that the most active compound versus lymphoma cells from Series 1 (compound 6) and two of the even more active ones from Series 2 (compounds 16 and 17) are in fact less toxic than MDMA to SH-SY5Y: a catecholaminergic neuroblastoma cell line that is used to model MDMA neurotoxicity. The same study also shows compound 6 having diminished psychoactivity when compared with MDMA in the prepulse inhibition of the acoustic startle reflex test in Wistar rats [11]. Furthermore, in the present study, while constituent cells of derived lines from all B-cell malignancies proved susceptible to one or more of the analogues tested, the relative level of sensitivity to a given compound could be quite different depending upon the cell line targeted indicating a degree of selectivity in the compounds' actions against lymphoma cell subtypes.…”

“…Screening against the sensitive L3055 cell line revealed no significant difference in the cells' response to compounds containing α-subsituents with either different steric (13)(14)(15)(16)(17) or stereoelectronic (9)(10)(11)(12) properties. Instead, the addition of further aromatic rings, thereby increasing the size of substituents at the α-carbon of MDMA, appeared a unifying factor to increasing potency: i.e.…”

“…Compounds MDMA and analogues with modified α-substituents were synthesized by reductive amination of the corresponding piperonyl ketones as described recently [11]. All target amines were converted to their hydrochlorides and were tested as such.…”

“…We now describe improved cytotoxic performance of MDMA analogues with modified α-substituents against a spectrum of B-cell malignancies giving attention to the mechanisms and pathways to cell death, including the impact of antiapoptotic Bcl-2. A companion study details in full the chemistry and synthesis of the analogues while providing evidence for diminished neurotoxicity and psychoactivity of selected compounds, together with a brief description of their rank potency in targeting a BL cell line [11].…”