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Anion transmembrane transport promoted by drug-like molecules: building a library of anion carriers inspired in Ataluren (PTC124)

Faculdade de Ciências da Universidade de Lisboa
Project classification

Scientific area

1.4 Chemical sciences

Discipline(s)

Organic chemistry

Project description

Project title

Anion transmembrane transport promoted by drug-like molecules: building a library of anion carriers inspired in Ataluren (PTC124)

Scientific Coordinator's name:

Vitor Félix

Scientific Coordinator's e-mail:

vitor.felix@ua.pt

Principal R&D Unit:

iBiMED (Universidade de Aveiro) ; Centro de Química e Bioquímica (CQB) -FCUL

Other R&D Units involved in the project:

Other R&D units involved in the project

Project keyword(s)

Cystic fibrosis; anion transporters; molecular dynamics; antitumor activity

Short abstract and comments

Ion transport across phospholipid cell membranes is crucial to several biological processes, such as nerve conduction and homeostasis maintenance. A combination of protein ion channels embedded in the membrane establishes and controls the ion concentrations inside and outside the cell. The dysfunction of these channels is currently linked with the occurrence of serious pathologies, commonly designated as channelopathies, including types of male infertility and the prominent cystic fibrosis (CF), caused by a defective transmembrane transport of the chloride and bicarbonate anions. Most of the current treatments for CF aim to manage the disease symptoms, while the cure remains a challenge. Indeed, only three synthetic molecules are known to modulate the defective anion channel: Ataluren, Lumacaftor and Ivacaftor. However, Ataluren treated patients have not shown major lung function improvement, thus emphasizing the need for alternative CF therapies, such as anion transporters. In this context, the goal is to synthesize an extensive library of anion transporters incorporating 1,2,4-, 1,3,4- or 1,2,5-oxadiazole isomers. One of the series of molecules containing only amide binding groups coupled by quinoline and pyridine ring motifs, the remaining four series have urea groups eventually mixed with thiourea and amide binding sites. Furthermore, specific series of molecules will be synthetized using the 2-nitrophenyl (thio)isocyanate as starting building block which linked to aromatic diamines produced molecules containing (thio)urea binding units. The key concepts bioisosteric replacement, scaffold hopping, lipophilicity and the anion binding will be explored together to obtain new transporters with pharmaceutical properties, which would represent a breakthrough in the field of anion transport Compound containing oxadiazole rings have been widely used in medicinal chemistry, as structural motifs for novel therapeutic molecules with a broad spectrum of biological activity, such as anti-inflammatory, analgesic, antimicrobial, antiviral, antitumor, and in Alzheimer disease, among others. Cytotoxicity studies will also be undertaken, given the antitumor potential already exhibited by other anion transporters.

Potential uses/indications

We establish for this project as a long-term goal the use of the molecules from our library in the anion channels replacement therapies.

Status

Ongoing

Partner Status: Seeking Partners?

Yes

Grant number (QREN, FP7, Eureka, etc)

1 MSc and 2 Postdocs

Last edited on

2016-11-21 17:44:36

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