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Bio-triggered triazenes : a novel approach to release alkylating agents

2022-09Doctoral thesis Open access
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datacite.subject.fosCiências Naturais::Ciências Químicaspt_PT
dc.contributor.advisorRocha, Maria de Jesus de Almeida Rainha Perry da Câmara Saldanha
dc.contributor.advisorMoreira, Rui Ferreira Alves
dc.contributor.advisorBernardes, Gonçalo José Lopes
dc.contributor.authorBraga, Cláudia Marisa Fernandes
dc.date.accessioned2023-06-28T10:59:18Z
dc.date.available2025-07-01T00:30:36Z
dc.date.issued2022-09
dc.date.submitted2022-06
dc.description.abstractGlioblastoma multiforme (GBM) is the most prevalent and invasive type of glioma, and patients present a median survival time of only 14 months after diagnosis. Temozolomide (TMZ) is a triazene-based prodrug approved for the treatment of high-grade brain tumours such as GBM, however, the highly heterogeneous and wide-spreading nature of glioma cells often disrupts its efficacy, resulting in resistance to chemotherapy, lack of selectivity for cancer cells and high tumour recurrence. Similarly to TMZ, 1-aryl-3-methyltriazenes are alkylating agents that have been developed in prodrug forms for targeted drug delivery, with reported anti-tumoral activities in the micromolar range against melanoma and glioblastoma cell lines. In this work, we aimed to target hypoxia which represents a key feature of GBM microenvironment with a set of nitroaromatic-based triazene prodrugs 14a-f, 22a-f and 47a-c designed to be selectively activated under hypoxia to release the cytotoxic methyldiazonium ion. The incorporation of different nitroaromatic triggers translated into variable rates of reduction towards E. coli nitroreductase NfsB. Biological evaluation under normoxic and hypoxic cultures of LN-229 and U-87MG glioblastoma cell lines revealed that compounds 14b, 14d and 14e exhibited a more pronounced cytotoxic effect than the same dose of TMZ, with minimal toxicity against normal primary fibroblast cells. Moreover, cell death by apoptosis and ROS production revealed to be increased in the presence of the selected prodrugs. Furthermore, we designed a dual function chromenone-based fluorescent probe to be activated under hypoxia, using NOBF4 for adequate diazonium salt stabilization before monomethyltriazene formation. However, the synthetic route still requires optimization and further examination on the apparent instability of the final dual-function molecule. Finally, hybrid compounds based on valproic acid and DNA-alkylating triazene moieties previously designed for GBM chemotherapy, were evaluated in GL261 cell line and compounds 67d and 67e shown to be remarkably more potent against glioma cells and more efficient in decreasing invasive cell properties than TMZ. In contrast to TMZ, which undergoes hydrolysis to release an alkylating metabolite, the valproate hybrids showed a low potential to alkylate DNA. This work contributed with two new categories of triazene prodrugs with confirmed in vitro anti-cancer activity. Altogether, these data validate the feasibility of the incorporation of triazenes in targeted-drug delivery platforms specifically designed to target glioblastoma multiforme.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2023-05-25T13:58:03Z No. of bitstreams: 1 scnd741219_td_Cláudia_Braga.pdf: 8412781 bytes, checksum: 746756648421ffcb08882d13fc2d8548 (MD5)en
dc.description.provenanceMade available in DSpace on 2023-06-28T10:59:18Z (GMT). No. of bitstreams: 1 scnd741219_td_Cláudia_Braga.pdf: 8412781 bytes, checksum: 746756648421ffcb08882d13fc2d8548 (MD5) Previous issue date: 2022-09en
dc.identifier.tid101579764pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/58377
dc.language.isoengpt_PT
dc.relationBIO-TRIGGERED TRIAZENES: A NOVEL APPROACH TO RELEASE ALKYLATING AGENTS
dc.relationPRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.subject1-aril-3-metiltriazenospt_PT
dc.subjectagentes alquilantespt_PT
dc.subjectglioblastoma multiformept_PT
dc.subjecthipóxiapt_PT
dc.subjectsistema de entrega direcionada de fármacospt_PT
dc.subject1-aryl-3-methyltriazenespt_PT
dc.subjectalkylating agentspt_PT
dc.subjectglioblastoma multiformept_PT
dc.subjecthypoxiapt_PT
dc.subjecttargeted-drug delivery systempt_PT
dc.titleBio-triggered triazenes : a novel approach to release alkylating agentspt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardTitleBIO-TRIGGERED TRIAZENES: A NOVEL APPROACH TO RELEASE ALKYLATING AGENTS
oaire.awardTitlePRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/FARH/PD%2FBD%2F135286%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/SAICTPAC%2F0019%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FMED-FAR%2F30266%2F2017/PT
oaire.fundingStreamFARH
oaire.fundingStream9471 - RIDTI
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream9471 - RIDTI
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.contributor.authoremailrepositorio@reitoria.ulisboa.pt
rcaap.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isProjectOfPublicationd27ab783-b8e8-44b7-a7a6-dc4dd93ba01b
relation.isProjectOfPublication7a25b129-19f8-47b3-a119-0c46d8e0bc70
relation.isProjectOfPublicationbb00962c-ed82-4d7a-bc37-61df49767d93
relation.isProjectOfPublicationa21e6964-b01b-421e-9356-1ff6579cdd5c
relation.isProjectOfPublicatione4e75623-bed4-4b63-851d-45ca8fa6794a
relation.isProjectOfPublication.latestForDiscoverybb00962c-ed82-4d7a-bc37-61df49767d93
thesis.degree.nameTese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2022pt_PT

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