Chiral metallohelices enantioselectively target hybrid human telomeric G-quadruplex DNA

Abstract

The design and synthesis of metal complexes that can specifically target DNA secondary structure has attracted considerable attention. Chiral metallosupramolecular complexes (e.g. helicates) in particular display unique DNA-binding behavior, however until recently few examples which are both water-compatible and enantiomerically pure have been reported. Herein we report that one metallohelix enantiomer Δ1a, available from a diastereoselective synthesis with no need for resolution, can enantioselectively stabilize human telomeric hybrid G-quadruplex and strongly inhibit telomerase activity with IC50 of 600 nM. In contrast, no such a preference is observed for the mirror image complex Λ1a. More intriguingly, neither of the two enantiomers binds specifically to human telomeric antiparallel G-quadruplex. To the best of our knowledge, this is the first example of one pair of enantiomers with contrasting selectivity for human telomeric hybrid G-quadruplex. Further studies show that Δ1a can discriminate human telomeric G-quadruplex from other telomeric G-quadruplexes.

Anticancer Activity and Cisplatin Binding Ability of Bis-Quinoline and Bis-Isoquinoline Derived [Pd2L4]4+ Metallosupramolecular Cages

“…Several groups have examined MSAs as drug delivery vectors (Therrien et al, 2008 ; Schmitt et al, 2012 ; Yi et al, 2012 ; Zheng et al, 2015 ; Samanta et al, 2016 , 2017 ; Bhat et al, 2017 ; Xu et al, 2017 ; Wang J.-F. et al, 2018 ; Yue et al, 2018 ). Additionally, MSAs have been shown to bind DNA (Oleksy et al, 2006 ; Garci et al, 2017 ; Zhao et al, 2017 ) and RNA (Phongtongpasuk et al, 2013 ; Malina et al, 2015 ), interact with proteins (Li et al, 2014 ; Mitchell et al, 2017 ) and have anticancer (Hotze et al, 2008 ; Faulkner et al, 2014 ; Grishagin et al, 2014 ; Dubey et al, 2015 ; Zheng et al, 2016 ; Allison et al, 2018 ) and antibacterial (Richards et al, 2009 ; Howson et al, 2012 ; Wang H. et al, 2018 ) properties.…”

Stabilization of human telomeric RNA G-quadruplex by the water-compatible optically pure and biologically-active metallohelices

“…The binding mode of the 5a – h was not fully resolved, however, the results from the experiments with 2Ap-labeled G-quadruplex and the cleavage by RNase A suggest that the metallohelices stack externally to the terminal G-quartet on the 5′-side of the TERRA G-quadruplex. Stacking interaction with the terminal G-quartet has been previously proposed for the binding of 5a with human telomeric DNA G-quadruplex 34 . In summary, our results show that, 5a – h metallohelices are potent stabilizers of TERRA G-quadruplex and act as inhibitors of reverse transcription on the template containing four repeats of human telomeric sequence.…”

“…Another example of a chiral metallohelical complex 5a (see structure in Fig. 1 A) capable of enantioselective stabilization of human telomeric hybrid DNA G-quadruplex and inhibition of telomerase activity was reported recently 34 . This compound developed by Scott and co-workers belongs to the class of cationic metallohelices that are based on helical arrays of fully-encapsulated Fe ions connected by different linking bridges (Fig.…”

Antiproliferative properties of iron supramolecular cylinders

“…In this respect, metallo-supramolecular cylinders such as metallohelicates show great potential [22][23][24][25][26][27]; however, their use in drug design is minimal [28], probably due to synthetic issues, their preparation often being more intricate than that of the (mono)metallic complexes normally used in the field. So far, metallo-supramolecular cylinders designed to interact with DNA (and RNA) via non-covalent bonds, have been obtained from nitrogen-containing ligands [29][30][31][32]. In the present study, two new triplestranded, iron(III) metallocylinders were prepared from oxygen-containing, dinucleating ligands, namely bis-β-diketones [33].…”