Potent Chlorambucil-Platinum(IV) Prodrugs
The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, <b>[Pt<sup>IV</sup>(H<sub>L</sub>)(A<sub>L</sub>)(OH)<sub>2</sub>](NO&l...
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/18/10471 |
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| author | Angelico D. Aputen Maria George Elias Jayne Gilbert Jennette A. Sakoff Christopher P. Gordon Kieran F. Scott Janice R. Aldrich-Wright |
| author_facet | Angelico D. Aputen Maria George Elias Jayne Gilbert Jennette A. Sakoff Christopher P. Gordon Kieran F. Scott Janice R. Aldrich-Wright |
| author_sort | Angelico D. Aputen |
| collection | DOAJ |
| description | The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, <b>[Pt<sup>IV</sup>(H<sub>L</sub>)(A<sub>L</sub>)(OH)<sub>2</sub>](NO<sub>3</sub>)<sub>2</sub></b> (where H<sub>L</sub> is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, A<sub>L</sub> is 1<i>S</i>,2<i>S</i>-diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, <b>PCLB</b>, <b>5CLB</b>, and <b>56CLB</b>, were characterized using high-performance liquid chromatography, nuclear magnetic resonance, ultraviolet-visible, circular dichroism spectroscopy, and electrospray ionization mass spectrometry. The prodrugs displayed remarkable antitumor potential across multiple human cancer cell lines compared to chlorambucil, cisplatin, oxaliplatin, and carboplatin, as well as their platinum(II) precursors, <b>PHEN<i>SS</i></b>, <b>5ME<i>SS</i></b>, and <b>56ME<i>SS</i></b>. Notably, <b>56CLB</b> was exceptionally potent in HT29 colon, Du145 prostate, MCF10A breast, MIA pancreas, H460 lung, A2780, and ADDP ovarian cell lines, with GI<sub>50</sub> values ranging between 2.7 and 21 nM. Moreover, significant production of reactive oxygen species was detected in HT29 cells after treatment with <b>PCLB</b>, <b>5CLB</b>, and <b>56CLB</b> up to 72 h compared to chlorambucil and the platinum(II) and (IV) precursors. |
| first_indexed | 2024-03-09T23:46:22Z |
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| id | doaj.art-0e8d8ac6cdd448829b6049a002158c29 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:46:22Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0e8d8ac6cdd448829b6049a002158c292023-11-23T16:42:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123181047110.3390/ijms231810471Potent Chlorambucil-Platinum(IV) ProdrugsAngelico D. Aputen0Maria George Elias1Jayne Gilbert2Jennette A. Sakoff3Christopher P. Gordon4Kieran F. Scott5Janice R. Aldrich-Wright6School of Science, Western Sydney University, Locked Bag 1797, Penrith South DC, Sydney, NSW 2751, AustraliaSchool of Science, Western Sydney University, Locked Bag 1797, Penrith South DC, Sydney, NSW 2751, AustraliaCalvary Mater Hospital, Waratah, NSW 2298, AustraliaCalvary Mater Hospital, Waratah, NSW 2298, AustraliaSchool of Science, Western Sydney University, Locked Bag 1797, Penrith South DC, Sydney, NSW 2751, AustraliaIngham Institute, Liverpool, NSW 2170, AustraliaSchool of Science, Western Sydney University, Locked Bag 1797, Penrith South DC, Sydney, NSW 2751, AustraliaThe DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, <b>[Pt<sup>IV</sup>(H<sub>L</sub>)(A<sub>L</sub>)(OH)<sub>2</sub>](NO<sub>3</sub>)<sub>2</sub></b> (where H<sub>L</sub> is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, A<sub>L</sub> is 1<i>S</i>,2<i>S</i>-diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, <b>PCLB</b>, <b>5CLB</b>, and <b>56CLB</b>, were characterized using high-performance liquid chromatography, nuclear magnetic resonance, ultraviolet-visible, circular dichroism spectroscopy, and electrospray ionization mass spectrometry. The prodrugs displayed remarkable antitumor potential across multiple human cancer cell lines compared to chlorambucil, cisplatin, oxaliplatin, and carboplatin, as well as their platinum(II) precursors, <b>PHEN<i>SS</i></b>, <b>5ME<i>SS</i></b>, and <b>56ME<i>SS</i></b>. Notably, <b>56CLB</b> was exceptionally potent in HT29 colon, Du145 prostate, MCF10A breast, MIA pancreas, H460 lung, A2780, and ADDP ovarian cell lines, with GI<sub>50</sub> values ranging between 2.7 and 21 nM. Moreover, significant production of reactive oxygen species was detected in HT29 cells after treatment with <b>PCLB</b>, <b>5CLB</b>, and <b>56CLB</b> up to 72 h compared to chlorambucil and the platinum(II) and (IV) precursors.https://www.mdpi.com/1422-0067/23/18/10471<b>PHEN<i>SS</i></b><b>5ME<i>SS</i></b><b>56ME<i>SS</i></b>DNAchlorambucilplatinum(II) |
| spellingShingle | Angelico D. Aputen Maria George Elias Jayne Gilbert Jennette A. Sakoff Christopher P. Gordon Kieran F. Scott Janice R. Aldrich-Wright Potent Chlorambucil-Platinum(IV) Prodrugs International Journal of Molecular Sciences <b>PHEN<i>SS</i></b> <b>5ME<i>SS</i></b> <b>56ME<i>SS</i></b> DNA chlorambucil platinum(II) |
| title | Potent Chlorambucil-Platinum(IV) Prodrugs |
| title_full | Potent Chlorambucil-Platinum(IV) Prodrugs |
| title_fullStr | Potent Chlorambucil-Platinum(IV) Prodrugs |
| title_full_unstemmed | Potent Chlorambucil-Platinum(IV) Prodrugs |
| title_short | Potent Chlorambucil-Platinum(IV) Prodrugs |
| title_sort | potent chlorambucil platinum iv prodrugs |
| topic | <b>PHEN<i>SS</i></b> <b>5ME<i>SS</i></b> <b>56ME<i>SS</i></b> DNA chlorambucil platinum(II) |
| url | https://www.mdpi.com/1422-0067/23/18/10471 |
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