期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 66, 期 5, 页码 3393-3410出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01895
关键词
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A series of autophagy-targeted platinum(IV) conjugates incorporating an autophagy activator, clioquinol (CLQ), were designed. Among them, complex 5 with potent antitumor properties was selected as a candidate. Complex 5 showed significant antimetastatic properties both in vitro and in vivo by inducing DNA damage, promoting autophagy, and activating immunity. Key proteins associated with angiogenesis and metastasis, such as VEGFA, MMP-9, and CD34, were downregulated.
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 gamma-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-1 alpha/ Beclin1 pathway. The T-cell immunity was elevated by restraining the PD-L1 expression and subsequently increasing CD3+ and CD8+ 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.
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