Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure–Activity Relationship Study
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 (<b>1</b>–&...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/17/13301 |
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| author | Man Kshetri Wjdan Jogadi Suha Alqarni Payel Datta May Cheline Arpit Sharma Tyler Betters Deonya Broyles Yao-Rong Zheng |
| author_facet | Man Kshetri Wjdan Jogadi Suha Alqarni Payel Datta May Cheline Arpit Sharma Tyler Betters Deonya Broyles Yao-Rong Zheng |
| author_sort | Man Kshetri |
| collection | DOAJ |
| description | 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 (<b>1</b>–<b>9</b>) 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 <b>2</b> and <b>7</b>) as model compounds: one (<b>2</b>) with a hydrophilic polyethylene glycol (PEG) head group, and the other (<b>7</b>) 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 <b>2</b>, 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 <b>7</b>, 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. |
| first_indexed | 2024-03-10T23:21:56Z |
| format | Article |
| id | doaj.art-d52a8599c3b348e08afb88d7a84d8106 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:21:56Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d52a8599c3b348e08afb88d7a84d81062023-11-19T08:15:20ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124171330110.3390/ijms241713301Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure–Activity Relationship StudyMan Kshetri0Wjdan Jogadi1Suha Alqarni2Payel Datta3May Cheline4Arpit Sharma5Tyler Betters6Deonya Broyles7Yao-Rong Zheng8Department of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USADepartment of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USADepartment of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USADepartment of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USADepartment of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USADepartment of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USADepartment of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USADepartment of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USADepartment of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USAWe 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 (<b>1</b>–<b>9</b>) 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 <b>2</b> and <b>7</b>) as model compounds: one (<b>2</b>) with a hydrophilic polyethylene glycol (PEG) head group, and the other (<b>7</b>) 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 <b>2</b>, 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 <b>7</b>, 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.https://www.mdpi.com/1422-0067/24/17/13301platinum(IV) prodrugsstructure–activity relationshipanticancer |
| spellingShingle | Man Kshetri Wjdan Jogadi Suha Alqarni Payel Datta May Cheline Arpit Sharma Tyler Betters Deonya Broyles Yao-Rong Zheng Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure–Activity Relationship Study International Journal of Molecular Sciences platinum(IV) prodrugs structure–activity relationship anticancer |
| title | Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure–Activity Relationship Study |
| title_full | Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure–Activity Relationship Study |
| title_fullStr | Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure–Activity Relationship Study |
| title_full_unstemmed | Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure–Activity Relationship Study |
| title_short | Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure–Activity Relationship Study |
| title_sort | exploring the impact of head group modifications on the anticancer activities of fatty acid like platinum iv prodrugs a structure activity relationship study |
| topic | platinum(IV) prodrugs structure–activity relationship anticancer |
| url | https://www.mdpi.com/1422-0067/24/17/13301 |
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