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Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure-Activity Relationship Study.
Kshetri, Man; Jogadi, Wjdan; Alqarni, Suha; Datta, Payel; Cheline, May; Sharma, Arpit; Betters, Tyler; Broyles, Deonya; Zheng, Yao-Rong.
Afiliación
  • Kshetri M; Department of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USA.
  • Jogadi W; Department of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USA.
  • Alqarni S; Department of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USA.
  • Datta P; Department of Chemistry, University of Bisha, Bisha 67714, Saudi Arabia.
  • Cheline M; Department of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USA.
  • Sharma A; Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
  • Betters T; Department of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USA.
  • Broyles D; Department of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USA.
  • Zheng YR; Department of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USA.
Int J Mol Sci ; 24(17)2023 Aug 27.
Article en En | MEDLINE | ID: mdl-37686109
We conducted the first comprehensive investigation on the impact of head group modifications on the anticancer activities of fatty-acid-like Pt(IV) prodrugs (FALPs), which are a class of platinum-based metallodrugs that target mitochondria. We created a small library of FALPs (1-9) with diverse head group modifications. The outcomes of our study demonstrate that hydrophilic modifications exclusively enhance the potency of these metallodrugs, whereas hydrophobic modifications significantly decrease their cytotoxicity. To further understand this interesting structure-activity relationship, we chose two representative FALPs (compounds 2 and 7) as model compounds: one (2) with a hydrophilic polyethylene glycol (PEG) head group, and the other (7) with a hydrophobic hydrocarbon modification of the same molecular weight. Using these FALPs, we conducted a targeted investigation on the mechanism of action. Our study revealed that compound 2, with hydrophilic modifications, exhibited remarkable penetration into cancer cells and mitochondria, leading to subsequent mitochondrial and DNA damage, and effectively eradicating cancer cells. In contrast, compound 7, with hydrophobic modifications, displayed a significantly lower uptake and weaker cellular responses. The collective results present a different perspective, indicating that increased hydrophobicity may not necessarily enhance cellular uptake as is conventionally believed. These findings provide valuable new insights into the fundamental principles of developing metallodrugs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Profármacos Tipo de estudio: Prognostic_studies Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Profármacos Tipo de estudio: Prognostic_studies Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza