28494-51-1Relevant academic research and scientific papers
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.
Truncated S-MGBs: Towards a parasite-specific and low aggregation chemotype
Barrett, Michael P.,Brooke, Daniel P.,Carter, Katharine C.,Cross, Jasmine M.,Gillingwater, Kirsten,Giordani, Federica,Irving, Craig,Khalaf, Abedawn I.,McGee, Leah M. C.,Scott, Fraser J.,Shaw, Craig D.,Suckling, Colin J.
, p. 1391 - 1401 (2021)
This paper describes the design and synthesis of Strathclyde minor groove binders (S-MGBs) that have been truncated by the removal of a pyrrole ring in order to mimic the structure of the natural product, disgocidine. S-MGBs have been found to be active against many different organisms, however, selective antiparasitic activity is required. A panel of seven truncated S-MGBs was prepared and the activities examined against a number of clinically relevant organisms including several bacteria and parasites. The effect of the truncation strategy on S-MGB aggregation in aqueous environment was also investigated using 1H inspection and DOSY experiments. A lead compound, a truncated S-MGB, which possesses significant activity only against trypanosomes and Leishmania has been identified for further study and was also found to be less affected by aggregation compared to its full-length analogue. This journal is
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.
Carbohydrate-based DNA ligands: Sugar-oligoamides as a tool to study carbohydrate-nucleic acid interactions
Martin, Jason N.,Munoz, Eva M.,Schwergold, Caroline,Souard, Florence,Asensio, Juan Luis,Jimenez-Barbero, Jesus,Canada, Javier,Vicent, Cristina
, p. 9518 - 9533 (2005)
Sugar-oligoamides have been designed and synthesized as structurally simple carbohydrate-based ligands to study carbohydrate-DNA interactions. The general design of the ligands 1-3 has been done as to favor the bound conformation of Distamycin-type γ-linked covalent dimers which is a hairpin conformation. Indeed, NMR analysis of the sugar-oligoamides in the free state has indicated the presence of a percentage of a hairpin conformation in aqueous solution. The DNA binding activity of compounds 1-3 was confirmed by calf thymus DNA (ct-DNA) NMR titration. Interestingly, the binding of the different sugar-oligoamides seems to be modulated by the sugar configuration. Semiquantitative structural information about the DNA ligand complexes has been derived from NMR data. A competition experiment with Netropsin suggested that the sugar-oligoamide 3 bind to DNA in the minor groove. The NMR titrations of 1-3 with poly(dA-dT) and poly(dG-dC) suggested preferential binding to the ATAT sequence. TR-NOE NMR experiments for the sugar-oligoamide 3-ct-DNA complex both in D2O and H2O have confirmed the complex formation and given information on the conformation of the ligand in the bound state. The data confirmed that the sugar-oligoamide ligand is a hairpin in the bound state. Even more relevant to our goal, structural information on the conformation around the N-glycosidic linkage has been accessed. Thus, the sugar asymmetric centers pointing to the NH-amide and N-methyl rims of the molecule have been characterized.
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-fungal and anti-mycobacterial therapeutics
Scott, Fraser J.,Nichol, Ryan J.O.,Khalaf, Abedawn I.,Giordani, Federica,Gillingwater, Kirsten,Ramu, Soumya,Elliott, Alysha,Zuegg, Johannes,Duffy, Paula,Rosslee, Michael-Jon,Hlaka, Lerato,Kumar, Santosh,Ozturk, Mumin,Brombacher, Frank,Barrett, Michael,Guler, Reto,Suckling, Colin J.
, p. 561 - 572 (2017/05/24)
This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product distamycin, which were designed to probe antifungal and antimycobacterial activity. From th
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
An evaluation of Minor Groove Binders as anti-lung cancer therapeutics
Scott, Fraser J.,Puig-Sellart, Mireia,Khalaf, Abedawn I.,Henderson, Catherine J.,Westrop, Gareth,Watson, David G.,Carter, Katharine,Grant, M. Helen,Suckling, Colin J.
supporting information, p. 3478 - 3486 (2016/07/22)
A series of 47 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for anti-lung cancer activity by screening against the melanoma cancer cell line B16-F10. Five compounds have been found to possess significant activity, more so than a standard therapy, Gemcitabine. Moreover, one compound has been found to have an activity around 70-fold that of Gemcitabine and has a favourable selectivity index of greater than 125. Furthermore, initial studies have revealed this compound to be metabolically stable and thus it represents a lead for further optimisation towards a novel treatment for lung cancer.
Amide isosteres in structure-activity studies of antibacterial minor groove binders
Khalaf, Abedawn I.,Anthony, Nahoum,Breen, David,Donoghue, Gavin,MacKay, Simon P.,Scott, Fraser J.,Suckling, Colin J.
experimental part, p. 5343 - 5355 (2012/01/06)
Antibacterial minor groove binders related to the natural product, distamycin, are development candidates for novel antibiotics. Alkenes have been found to be effective substitutes for the isosteric amide links in some positions and alkyl groups larger th
Synthesis and biophysical studies of hairpin polyamides targeting the Brn-3b and GATA-3 transcriptional sites
Babu, Balaji,MacKay, Hilary,Prast, Abby,Dittenhafer, Kristin,Davis, Ryan,Tronrud, Christopher,Rice, Toni,Chavda, Sameer,Lee, Moses
scheme or table, p. 221 - 225 (2011/06/21)
Hairpin polyamide analogs of distamycin A ( 1 ) were designed and synthesized to evaluate their ability to bind 5 ' -ATAGA-3 ' and 5 ' -AGATA-3 ' sequences which are important elements for controlling the function of the Brn-3b and GATA-3 transcriptional factors, respectively. The hairpin polyamides are composed of pyrrole and imidazole units linked together via a γ -aminobutyrate (GABA) unit. Hairpins 2b (Py-Py-Im- γ -Py-Py-Py) and 2c (Im-Py-Py- γ -Py-Py-Py) were synthesized to target the respective Brn-3b and GATA-3 cognate sequences. Preliminary biophysical studies including thermal denaturation and circular dichroism were performed and the results ascertained the binding of hairpins 2a and 2b to their respective cognate DNA sequences.
