28494-51-1Relevant articles and documents
Selective: In vitro anti-cancer activity of non-alkylating minor groove binders
Nichol, Ryan J. O.,Khalaf, Abedawn I.,Sooda, Kartheek,Hussain, Omar,Griffiths, Hollie B. S.,Phillips, Roger,Javid, Farideh A.,Suckling, Colin J.,Allison, Simon J.,Scott, Fraser J.
, p. 1620 - 1634 (2019)
Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating Strathclyde Minor Groove Binders (S-MGBs), including 14 novel compounds, for in vitro anti-cancer activity against a human colon carcinoma cell line, a cisplatin-sensitive ovarian cancer cell line and a cisplatin-resistant ovarian cancer cell line. A human non-cancerous retinal epithelial cell line was used to measure selectivity of any response. We have identified several S-MGBs with activities comparable to cis-platin and carboplatin, but with better in vitro selectivity indices, particularly S-MGB-4, S-MGB-74 and S-MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our S-MGBs do not show cross resistance with cisplatin or carboplatin and that they likely have a different mechanism of action. Finally, we present an initial investigation into the mechanism of action of one compound from this class, S-MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our S-MGBs are unlikely to act through an alkylating or DNA damage response mechanism.
Sugar-oligoamides: Bound-state conformation and DNA minor-groove-binding description by TR-NOESY and differential-frequency saturation-transfer- difference experiments
Souard, Florence,Munoz, Eva,Penalver, Pablo,Badia, Concepcion,Del Villar-Guerra, Rafael,Asensio, Juan Luis,Jimenez-Barbero, Jesus,Vicent, Cristina
, p. 2435 - 2442 (2008)
Selective-frequency saturation-transfer-difference (STD) spectra allow the description of complexes established between minor-groove binders and long tracts of calf thymus DNA (ct-DNA). Two sets of experiments with selective saturation of either the H1′ or H4′/H5′/H5″ proton NMR regions of deoxyribose allow the description of the ligand residues close to the inner (H1′) and outer regions (H4′/H5′/H5″) of the minor groove of double-helical DNA. A series of complexes of sugar-oligoamides (2-6) with ct-DNA have been studied by both TR-NOESY and STD experiments. The binding mode of the complexes is similar to that of netropsin (1) and allows us to define a general binding mode for this family of ligands, in which an NH rim points towards the internal area (inner region) and a CH3 rim points towards the external part (outer region) of the minor groove of DNA. Also by means of both TR-NOESY and STD experiments, a description of the asymmetric centers of the sugar residue close to the inner and outer regions of the groove has been achieved. These results confirm that the sugar is responsible for the differences previously found in binding energetics.
Enhanced sequence specific recognition in the minor groove of DNA by covalent peptide dimers: Bis(pyridine-2-carboxamidonetropsin)(CH2)3-6
Mrksich, Milan,Dervan, Peter B.
, p. 9892 - 9899 (1993)
The designed peptide pyridine-2-carboxamidonetropsin (2-PyN) binds to the minor groove of double-helical DNA at two very different sequences, 5′-TTTTT-3′ and 5′-TGTCA-3′, with comparable energetics but quite different structures. 2-PyN likely binds the 5′-TTTTT-3′ site as a 1:1 complex, whereas 2-PyN binds 5′-TGTCA-3′ sites as a 2:1 complex. In order to enhance the binding affinity of 2-PyN for the 5′-TGTCA-3′ site, covalently linked dimers of 2-PyN have been synthesized wherein the nitrogens of the central pyrroles are connected with propyl, butyl, pentyl, and hexyl linkers. DNase I footprint titration experiments reveal that these bis(pyridine-2-carboxamidenetropsin)(CH2)3-6 peptides bind to a 5′-TGTCA-3′ site with binding affinities 10-fold greater than that of 2-PyN. By taking advantage of the different structures of peptides bound in the minor groove, the ratio of binding affinities of 2-PyN for 5′-TGTCA-3′ and 5′-TTTTT-3′ sites have been altered from 1:1 to 25:1.
An evaluation of Minor Groove Binders as anti-Trypanosoma brucei brucei therapeutics
Scott, Fraser J.,Khalaf, Abedawn I.,Giordani, Federica,Wong, Pui Ee,Duffy, Sandra,Barrett, Michael,Avery, Vicky M.,Suckling, Colin J.
, p. 116 - 125 (2016/04/19)
A series of 32 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for activity against Trypanosoma brucei brucei. Four compounds have been found to possess significant activity, in the nanomolar range, and represent hits
