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Development of Clioquinol Platinum(IV) Conjugates as Autophagy-Targeted Antimetastatic Agents.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2023 Mar 09; Vol. 66 (5), pp. 3393-3410. Date of Electronic Publication: 2023 Feb 22. - Publication Year :
- 2023
-
Abstract
- A series of autophagy-targeted antimetastatic clioquinol (CLQ) platinum(IV) conjugates were designed and prepared by incorporating an autophagy activator CLQ into the platinum(IV) system. Complex 5 with the cisplatin core bearing dual CLQ ligands with potent antitumor properties was screened out as a candidate. More importantly, it displayed potent antimetastatic properties both in vitro and in vivo as expected. Mechanism investigation manifested that complex 5 induced serious DNA damage to increase γ- H2AX and P53 expression and caused mitochondria-mediated apoptosis through the Bcl-2/Bax/caspase3 pathway. Then, it promoted prodeath autophagy by suppressing PI3K/AKT/mTOR signaling and activating the HIF-1α/Beclin1 pathway. The T-cell immunity was elevated by restraining the PD-L1 expression and subsequently increasing CD3 <superscript>+</superscript> and CD8 <superscript>+</superscript> T cells. Ultimately, metastasis of tumor cells was suppressed by the synergistic effects of DNA damage, autophagy promotion, and immune activation aroused by CLQ platinum(IV) complexes. Key proteins VEGFA, MMP-9, and CD34 tightly associated with angiogenesis and metastasis were downregulated.
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 66
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 36891739
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.2c01895