Synthesis, characterization, and anticancer activity of folate gamma-ferrocenyl conjugatest

Autor(es)

Bertuzzi, Diego L. ^[1] ; Perli, Gabriel ^[1] ; Braga, Carolyne B. ^[1] ; Ornelas, Catia ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Unicamp, Inst Chem, BR-13083861 Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: NEW JOURNAL OF CHEMISTRY; v. 44, n. 12, p. 4694-4703, MAR 28 2020.
• Citações Web of Science: 0

Resumo

The quest for alternative therapeutic agents with safe and effective profiles is one of the biggest challenges in oncology. FoLate-targeted therapy can deliver drugs selectively into maLignant ceLLs via the Fra receptor, whereas bioorganometaic chemistry offers potentiaL new drug candidates. Herein, novel foLate ry-ferrocene (ry-Fc) conjugates were synthesized through a regiospecific route by reacting amino terminated glutamate (au) ry-Fc residues with pteroyE azide (68-78% yield), and their in vitro anticancer activities were evaluated on human cells. The Fc units were attached to protected au residues through different Linkers using amide coupling and/or ``dick{''} reactions. Cyclic voLtammetry and UV-vis measurements showed that the triazole group conjugated to the Fc donates electrons to the ferrous center, which facilitates the oxidation of Fc that is responsible for the antiproliferative activity. These results were confirmed by the higher activity of foLate ry-triazoLeFc 21, with IC50 values at 25.4 p.M (3.2) on HeLa and 21.7 p.M (0.3) on MCF-7 cells. This compound was up to 4 -fold Less toxic to healthy PNT2 ceLLs and Fra-negative PC -3 cancer cells. Blocking experiments with an excess of free folic acid inhibited the foLate activity suggesting their specific uptake via Fra. au residue analogs of foLates, but Lacking the pteroyE moiety, were much Less toxic to cancer ceLLs than foLates. Hence, foLate ry-Fcs are potentiaL anticancer drug candidates due to their selectivity and enhanced cytotoxicity against Fra-positive maLignant cells. (AU)

• Processo FAPESP: 18/02093-0 - Desenvolvimento de novos nanomateriais para aplicações em nanomedicina
• Beneficiário: Cátia Cristina Capêlo Ornelas Megiatto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/04929-0 - Desenvolvimento de biosensores para detecção instantânea de proteínas e de células cancerígenas, para aplicação em biópsias on-site
• Beneficiário: Diego Luan Bertuzzi
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 17/06146-8 - Desenvolvimento de nanocarregadores baseados em dendrímeros e nanopartículas poliméricas para a vetorização seletiva da goniotalamina, piplartina e monastrol
• Beneficiário: Carolyne Brustolin Braga
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado