Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia

Abstract

A parthenolide-derivative with favourable pharmacokinetic properties and good activity against drug-resistant chronic lymphocytic leukaemia is reported.

Aniline-containing derivatives of parthenolide: Synthesis and anti-chronic lymphocytic leukaemia activity

“…The alamarBlue® assay was employed to measure their in vitro anti-leukaemic and LC 50 values were determined using CalcuSyn (Biosoft) software, Table 3 . The LC 50 values of parthenolide ( 1 ), 2a and 2b are consistent with previously published reports ( Table 3 , 4.6, 3.4 and 5.3 μM, entries 1, 2 and 3 respectively) [ 9 ]. The most active aniline derivatives were phenol-containing 3b , 3c and 3o LC 50 values of 12.5, 11.7 and 12.9 μM respectively ( Table 3 , entries 5, 6 and 18).…”

“…Inspired by the work of Neelakantan et al . in identifying compound 2a as a promising NF-κB inhibitor [ 28 ], the co-authors of this report had previously identified compound 2b as a potential anti-CLL therapy [ 8 , 9 ], which showed improved drug metabolism and pharmacokinetics (DMPK) properties. To the best of our knowledge the anti-leukaemic activity of aniline-derivatisation on parthenolide has not previously been addressed.…”

“…Whilst the addition of primary and secondary amines to parthenolide generally proceeds smoothly to give compounds 2 (reactions between 1 and amine in a range of solvents) [ 9 , 27 , 28 ], it was not possible, in our hands, to so readily react parthenolide with primary or secondary aniline derivatives to form analogous products 3 . As such the challenge to deliver and probe the anti-leukaemic activity of the under explored aniline derivatives of parthenolide ( 3 ) was embarked upon.…”

“…Parthenolide ( 1 ) is a natural product readily extracted from varieties of the plant feverfew (Tanacetum parthenium) [ [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] ] and has been widely reported to display promising activity against various diseases including types of cancer [ [16] , [17] , [18] , [19] , [20] , [21] ]. Mechanistically, parthenolide targets leukaemia cells by depleting glutathione and by alkylating Cys38 of NF-kB to inhibit DNA-binding [ 22 , 23 ].…”

“…Our team has previously utilised this approach to generate a library of parthenolide derivatives from which compound 2b ( Fig. 1 ), a promising lead in addressing CLL, was identified [ 9 ]. Among reported amine derivatives of parthenolide, to the best of our knowledge [ 40 ], there are no reports of analogous N -aryl (aniline) derivatives ( 3 , Fig.…”