Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors: Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model

Depauw, Sabine; Lambert, M.; Jambon, Samy; Paul, A.; Peixoto, Paul; Nhili, Raja; Marongiu, Laura; Figeac, Martin; Dassi, Christelle; Paul-Constant, Charles; Billoré, Benjamin; Kumar, Arvind; Farahat, Abdelbasset A.; Ismail, Mohamed A.; Mineva, Ekaterina M.; Sweat, Daniel P.; Stephens, Chad E.; Boykin, David W.; David-Cordonnier, Marie-Hélène

doi:10.1021/acs.jmedchem.8b01448

Cited by 34 publications

(34 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For HAT, however, the successes that have occurred with other compounds (see below) indicate that the diamidines are unlikely to be resurrected for future work. However, because of their diverse and intriguing biological activities [44], it is likely to see them re-emerging for other conditions in the future [45].…”

Section: Clinical Trials Of Pafuramidinementioning

confidence: 99%

“…Furamidine, like other diamidines, binds to the minor groove of the DNA double helix [28,45]. The ability to bind is structure-dependent, and intriguing work has aimed to tailor this binding to specific DNA sequences, including regulatory elements [44], with a view to controlling gene expression in, for example, human cancer cells. Furamidine is fluorescent, and its accumulation in trypanosomes shows binding to both the kinetoplast (mitochondrial DNA) and nuclear DNA, as well as its accumulation in vesicles assumed to be acidocalcisomes [46].…”

Section: Pafuramidine: Mode Of Action and Resistance Riskmentioning

confidence: 99%

See 1 more Smart Citation

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

et al. 2020

View full text Add to dashboard Cite

The twentieth century ended with human African trypanosomiasis (HAT) epidemics raging across many parts of Africa. Resistance to existing drugs was emerging, and many programs aiming to contain the disease had ground to a halt, given previous success against HAT and the competing priorities associated with other medical crises ravaging the continent. A series of dedicated interventions and the introduction of innovative routes to develop drugs, involving Product Development Partnerships, has led to a dramatic turnaround in the fight against HAT caused by Trypanosoma brucei gambiense. The World Health Organization have been able to optimize the use of existing tools to monitor and intervene in the disease. A promising new oral medication for stage 1 HAT, pafuramidine maleate, ultimately failed due to unforeseen toxicity issues. However, the clinical trials for this compound demonstrated the possibility of conducting such trials in the resource-poor settings of rural Africa. The Drugs for Neglected Disease initiative (DNDi), founded in 2003, has developed the first all oral therapy for both stage 1 and stage 2 HAT in fexinidazole. DNDi has also brought forward another oral therapy, acoziborole, potentially capable of curing both stage 1 and stage 2 disease in a single dosing. In this review article, we describe the remarkable successes in combating HAT through the twenty first century, bringing the prospect of the elimination of this disease into sight.

show abstract

Section: Clinical Trials Of Pafuramidinementioning

confidence: 99%

Section: Pafuramidine: Mode Of Action and Resistance Riskmentioning

confidence: 99%

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A mixture of 5-(4-cyanophenyl)-2-bromo furan 1 (1.23 g, 0.005 mole) and 4-methoxyphenyl boronic acid (0.93 g, 0.006 mole) in 75 ml dioxane under nitrogen was added K 2 CO 3 (1.38 g, 0.01 mole, in 5 ml H 2 O), followed by Pd(PPh 3 ) 4 0.12 g (0.0001 mole) and the solution was heated under reflux for 12-24 h (tlc monitored). The solvent was removed under reduced pressure, solid filtered, washed with hexane and dried in air.…”

Section: Chemistry Of New Compounds From David Boykin Laboratorymentioning

confidence: 99%

Positively selected modifications in the pore of TbAQP2 allow pentamidine to enterTrypanosoma brucei

Al-Ghamdi¹,

Munday²,

Campagnaro³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

31Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to 32 pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively 33 selected for increased pore size from a common ancestor aquaporin. We demonstrate that 34 TbAQP2's unique architecture permits pentamidine permeation through its central pore and 35 show how specific mutations in highly conserved motifs affect drug permeation. Introduction 36 of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. 37 Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically 38 favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally 39 strictly impermeable for ionic species. We also identify the structural determinants that make 40 pentamidine a permeant but exclude most other diamidine drugs. Our results have wide-41 ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. 42Moreover, these new insights in aquaporin permeation may allow the pharmacological 43 exploitation of other members of this ubiquitous gene family. 44 45 Keywords: 46 Drug transport / Aquaporin / evolution of membrane proteins / Trypanosoma brucei / 47 109 endocytosis rate and the rate of pentamidine uptake. Our results unequivocally show that 110 pentamidine permeates directly through the central pore of TbAQP2 and that uptake is 111 dependent on the microbial membrane potential. Having identified the essential 112 characteristics that allow the transport of large, flexible molecules through TbAQP2, this 113 should now allow the evaluation of aquaporins in other species for similar adaptations.114 7 Results 115 116 12. Investigation of the structural determinants of AQP2 for pentamidine transport 117 1.1. Positive selection for pore size 118 In T. brucei, the AQP2 and AQP3 genes are arranged as a tandem pair on chromosome 10 119 and have 74% amino acid identity. Whereas TbAQP2 clearly mediates pentamidine uptake, 120 TbAQP3 does not (Baker et al, 2012; Munday et al, 2014), nor do various chimeric AQP2/3 121 rearrangements that give rise to pentamidine resistance (Munday et al, 2014; Graf et al, 122 2015). To investigate the origin of the AQP2 gene, a phylogenetic analysis of AQPs in 123 African trypanosomes was performed. The number of aquaporin genes varies: there is a 124 single aquaporin in T. vivax and T. congolense, two in T. suis and three in T. brucei and its 125 derivatives (Supplemental Fig. 1A). The most probable tree (Supplemental Fig. 1B) is 126 consistent with the evolutionary history of the four species (Hutchinson & Gibson, 2015) and 127 indicates AQP1 as the ancestral AQP present in all trypanosome species. A duplication 128 occurred in the common ancestor of T. suis and T. brucei after divergence from T. 129 congolense and a further duplication, to form AQP2 and AQP3, in the ancestor of T. 130 brucei after divergence from T. suis. Multiple alignment (Supplemental Fig. 1A) shows that 131 the classical NPA/NPA a...

show abstract

“…Synthesis of the bisnitrile compounds (5 a-n). [56,57] Sodium metabisulphite (1.14 g, 6mmol) was added to as olution of the diamine 3a-k (3 mmol) and the aldehyde 4a-d (3 mmol) in DMSO (10 mL) and the mixture was heated at 140 8Cf or 30 min. The reaction mixture was poured into water,f iltered and dried.…”

Section: Chemistrymentioning

confidence: 99%

Small Sequence‐Sensitive Compounds for Specific Recognition of the G⋅C Base Pair in DNA Minor Groove

Farahat

Guo

Shoeib

et al. 2020

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

A series of small diamidines with thiophene and modified N‐alkylbenzimidazole σ‐hole module represent specific binding to single G⋅C base pair (bp) DNA sequence. The variation of N‐alkyl or aromatic rings were sensitive to microstructures of the DNA minor groove. Thirteen new compounds were synthesized to test their binding affinity and selectivity. The dicyanobenzimidazoles needed to synthesize the target diamidines were made via condensation/cyclization reactions of different aldehydes with different 3‐amino‐4‐(alkyl‐ or phenyl‐amino) benzonitriles. The final diamidines were synthesized using lithium bis‐trimethylsilylamide (LiN[Si(CH3)3]2) or Pinner methods. The newly synthesized compounds showed strong binding and selectivity to AAAGTTT compared to similar sequences AAATTT and AAAGCTTT investigated by several biophysical methods including biosensor‐SPR, fluorescence spectroscopy, DNA thermal melting, ESI‐MS spectrometry, circular dichroism, and molecular dynamics. The binding affinity results determined by fluorescence spectroscopy are in accordance with those obtained by biosensor‐SPR. These small size single G⋅C bp highly specific binders extend the compound database for future biological applications.

show abstract

Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors: Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model

Abstract: Most transcription factors were for a long time considered as undruggable targets due to the absence of binding pockets for direct targeting. HOXA9, implicated in acute myeloid leukemia, is one of them. To date, only indirect targeting of HOXA9 expression or multi-target HOX/PBX

Cited by 34 publications

References 104 publications

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

Positively selected modifications in the pore of TbAQP2 allow pentamidine to enterTrypanosoma brucei

Small Sequence‐Sensitive Compounds for Specific Recognition of the G⋅C Base Pair in DNA Minor Groove

Contact Info

Product

Resources

About