Succinamide derivatives of melampomagnolide B and their anti-cancer activities

A series of succinamide derivatives of melampomagnolide B have been synthesized by coupling MMB monosuccinate (2) with various heterocyclic amines to afford compounds 3a-3l. MMB monosuccinate was also reacted with terminal diaminoalkanes to afford dimeric succinamido analogs of MMB (4a-4h). These succinamide analogs of MMB were evaluated for their anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 3d-3i and dimers 4f-4g exhibited promising anti-cancer activity with GI(50) values ranging from 0.28 to 33.5 mu M against most of the cell lines in the panel. The dimeric analogs 4f and 4g were identified as lead compounds with GI(50) values in the nanomolar range (GI(50) = 280-980 nM) against several cell lines in the panel; i.e. leukemia cell lines CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226 and SR; and solid tumor cell lines NCI-H522 (non-small cell lung cancer), SW-620 and HCT-116 (colon cancer), LOX IMVI (melanoma), RXF 393 (renal cancer), and MCF7, BT-549 and MDA-MB-468 (breast cancer). Succinamide analogs 3a, 3c-3l and 4b-4h were also evaluated for their apoptotic activity against M9-ENL1 acute myelogenous leukemia cells; compounds 3h-3j and 4g were equipotent with parthenolide, exhibiting LC50 values in the range 4.1-8.1 mu M. Molecular docking studies indicate that these molecules interact covalently with the highly conserved Cys-46 residue of the N-terminal lobe (1-109) of human IKK beta to inhibit the NF-kappa B transcription factor complex, resulting in down-regulation of anti-apoptotic genes under NF kappa B control. (C) 2017 Elsevier Ltd. All rights reserved.