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The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Medicinal Chemistry, Uppsala University, BMC, Uppsala, Sweden.ORCID-id: 0000-0001-7691-4392
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.ORCID-id: 0000-0001-8089-2333
Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
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2023 (Engelska)Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 248, artikel-id 115103Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

G-quadruplex (G4) DNA structures are involved in central biological processes such as DNA replication and transcription. These DNA structures are enriched in promotor regions of oncogenes and are thus promising as novel gene silencing therapeutic targets that can be used to regulate expression of oncoproteins and in particular those that has proven hard to drug with conventional strategies. G4 DNA structures in general have a well-defined and hydrophobic binding area that also is very flat and featureless and there are ample examples of G4 ligands but their further progression towards drug development is limited. In this study, we use synthetic organic chemistry to equip a drug-like and low molecular weight central fragment with different side chains and evaluate how this affect the compound's selectivity and ability to bind and stabilize G4 DNA. Furthermore, we study the binding interactions of the compounds and connect the experimental observations with the compound's structural conformations and electrostatic potentials to understand the basis for the observed improvements. Finally, we evaluate the top candidates' ability to selectively reduce cancer cell growth in a 3D co-culture model of pancreatic cancer which show that this is a powerful approach to generate highly active and selective low molecular weight G4 ligands with a promising therapeutic window.

Ort, förlag, år, upplaga, sidor
Elsevier, 2023. Vol. 248, artikel-id 115103
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
URN: urn:nbn:se:umu:diva-202112DOI: 10.1016/j.ejmech.2023.115103ISI: 000922160800001Scopus ID: 2-s2.0-85146280645OAI: oai:DiVA.org:umu-202112DiVA, id: diva2:1723074
Forskningsfinansiär
Kempestiftelserna, SMK-1632Vetenskapsrådet, 2017–05235Vetenskapsrådet, 2017- 01531Sveriges läkarförbund, SLS-890521Region Västerbotten, RV-930167Knut och Alice Wallenbergs StiftelseMarianne och Marcus Wallenbergs Stiftelse, 2020.0189Cancerfonden, 20 1339 PjFCancerforskningsfonden i Norrland, LP 21–2298Cancerforskningsfonden i Norrland, LP 22–2332
Anmärkning

Originally included in thesis in manuscript form.

Tillgänglig från: 2023-01-02 Skapad: 2023-01-02 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
Ingår i avhandling
1. Redefining the essential molecular aspects that drive interactions between small molecules and G-quadruplex DNA
Öppna denna publikation i ny flik eller fönster >>Redefining the essential molecular aspects that drive interactions between small molecules and G-quadruplex DNA
2023 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Omvärdering av de centrala molekylära aspekterna som styr interaktionen mellan små molekyler och G-quadruplex DNA
Abstract [en]

G-Quadruplex (G4) structures are secondary nucleic acid structures located in guanine-rich regions of DNA and RNA sequences, involved in gene regulation and cellular maintenance. Efforts to target G4s in a therapeutic setting are scarce, mainly due to vague details about the binding interactions between the ligands and the G4 structure combined with the lack of emphasis on drug-like properties early in the ligand development process. Furthermore, the ability to target specific G4 structures with small drug-like molecules remains a big challenge to overcome in the field. In this thesis, extensive organic synthesis developments coupled with computational-aided design and orthogonal in vitro assays has been used in tandem to reveal in-depth knowledge about ligand-to-G4 interactions. First, a macrocyclic approach was applied to design and discover novel G4 ligands which showed that macrocycles offer a solid foundation for ligand design. Next, computational tools to optimise the macrocyclic molecular conformation were used based on the macrocycles' abilities to stack on the G4 surface. In addition, macrocyclic, and non-macrocyclic ligands that bound G4 with high potency were shown to correlate with electron-deficient electrostatic potential (ESP) maps. The frequent inclusion of cationic residues in G4 ligands and their enhancement on ligand-to-G4 binding was, thereof, ascribed to their impact on the electrostatic character of the ligands' arene-arene interactions with the G4 surface, and not through direct electrostatic ionic interactions. In addition, the dispersion energetic component in the arene-arene interactions between the G4 ligand and the G4 was discovered to be paramount for ligand-to-G4 binding. The implementation of these descriptors in practice resulted in the discovery of potent G4 binders with adequate pharmacokinetic (PK) properties, accentuating the significance of understanding the molecular interactions between ligands and G4s in rational ligand design. Finally, a G4 ligand conjugated to an oligonucleotide was demonstrated as a modular approach to achieve selective binding of a ligand to a specific G4 structure. 

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2023. s. 73
Nyckelord
G-Quadruplexes, DNA, Oncogenes, G4 ligands, heterocycles, macrocycles, organic synthesis, molecular interactions, rational compound design, medicinal chemistry.
Nationell ämneskategori
Organisk kemi
Forskningsämne
läkemedelskemi; organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-202119 (URN)978-91-7855-970-1 (ISBN)978-91-7855-969-5 (ISBN)
Disputation
2023-01-27, KB.E3.03 (stora hörsalen), KBC-huset, Universitetsområdet, 907 36 Umeå, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2023-01-05 Skapad: 2023-01-02 Senast uppdaterad: 2023-01-02Bibliografiskt granskad

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Bhuma, NareshChand, KaramAndréasson, MånsMason, James E.Das, Rabindra NathÖhlund, DanielChorell, Erik

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Bhuma, NareshChand, KaramAndréasson, MånsMason, James E.Das, Rabindra NathÖhlund, DanielChorell, Erik
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Kemiska institutionenInstitutionen för strålningsvetenskaperWallenberg centrum för molekylär medicin vid Umeå universitet (WCMM)Onkologi
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European Journal of Medicinal Chemistry
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