Platinum binding preferences dominate the binding of novel polyamide amidine anthraquinone platinum(<scp>ii</scp>) complexes to DNA

Lo, Anthony T. S.; Chen, Jon K.; Murray, Vincent; Todd, Matthew H.; Hambley, Trevor W.

doi:10.1039/d1dt03539h

Cited by 2 publications

(3 citation statements)

References 33 publications

(38 reference statements)

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“…Several studies have revealed that various tricyclic and tetracyclic backbone‐based derivatives may extend their antitumor activities through DNA‐intercalating activities and topoisomerase blocking capabilities 11–15 . It has been unveiled that TOP–DNA covalent complexes from either TOP I‐specific poison or TOP II‐specific poison are able to trigger 26S proteasome‐involved degradation indicated as TOP downregulation 16–18 .…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have revealed that various tricyclic and tetracyclic backbone-based derivatives may extend their antitumor activities through DNA-intercalating activities and topoisomerase blocking capabilities. [11][12][13][14][15] It has been unveiled that TOP-DNA covalent complexes from either TOP I-specific poison or TOP II-specific poison are able to trigger 26S proteasome-involved degradation indicated as TOP downregulation. [16][17][18] Our examination demonstrated that WC-A compounds selectively induced the downregulation of both TOP IIα and TOP IIβ in a concentrationdependent manner but had no impact on TOP I protein expression (Figure 2A).…”

Section: Wc-a Derivatives Display Anticancer Activities Through the I...mentioning

confidence: 99%

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Mechanistic study of dual‐function inhibitors targeting topoisomerase II and Rad51‐mediated DNA repair pathway against castration‐resistant prostate cancer

et al. 2023

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BackgroundCastration‐resistant prostate cancer (CRPC) is refractory to hormone treatment and the therapeutic options are continuously advancing. This study aims to discover the anti‐CRPC effects and underlying mechanisms of small‐molecule compounds targeting topoisomerase (TOP) II and cellular components of DNA damage repair.MethodsCell proliferation was determined in CRPC PC‐3 and DU‐145 cells using anchorage‐dependent colony formation, sulforhodamine B assay and flow cytometric analysis of CFSE staining. Flow cytometric analyses of propidium iodide staining and JC‐1 staining were used to examine the population of cell‐cycle phases and mitochondrial membrane potential, respectively. Nuclear extraction was performed to detect the nuclear localization of cellular components in DNA repair pathways. Protein expressions were determined using Western blot analysis.ResultsA series of azathioxanthone‐based derivatives were synthesized and examined for bioactivities in which WC‐A13, WC‐A14, WC‐A15, and WC‐A16 displayed potent anti‐CRPC activities in both PC‐3 and DU‐145 cell models. These WC‐A compounds selectively downregulated both TOP IIα and TOP IIβ but not TOP I protein expression. WC‐A13, WC‐A14, and WC‐A15 were more potent than WC‐A16 on TOP II inhibition, mitochondrial dysfunction, and induction of caspase cascades indicating the key role of amine‐containing side chain of the compounds in determining anti‐CRPC activities. Furthermore, WC‐A compounds induced an increase of γH2AX and activated ATR‐Chk1 and ATM‐Chk2 signaling pathways. P21 protein expression was also upregulated by WC‐A compounds in which WC‐A16 showed the least activity. Notably, WC‐A compounds exhibited different regulation on Rad51, a major protein in homologous recombination of DNA in double‐stranded break repair. WC‐A13, WC‐A14, and WC‐A15 inhibited, whereas WC‐A16 induced, the nuclear translocation of Rad51.ConclusionThe data suggest that WC‐A compounds exhibit anti‐CRPC effects through the inhibition of TOP II activities, leading to mitochondrial stress‐involved caspase activation and apoptosis. Moreover, WC‐A13, WC‐A14, and WC‐A15 but not WC‐A16 display inhibitory activities of Rad51‐mediated DNA repair pathway which may increase apoptotic effect of CRPC cells.

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Section: Resultsmentioning

confidence: 99%

Section: Wc-a Derivatives Display Anticancer Activities Through the I...mentioning

confidence: 99%

Mechanistic study of dual‐function inhibitors targeting topoisomerase II and Rad51‐mediated DNA repair pathway against castration‐resistant prostate cancer

et al. 2023

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“…[3][4][5][6] In addition, the next generation of platinum-based anticancer drugs with more remarkable clinical efficacy are being pursued. [7][8][9][10][11][12] Among the drug development plans, a platinum(IV)-based prodrug strategy has attracted the most attention from researchers. [13][14][15][16][17][18] By rationally adding the two additional axial ligands to the platinum(II) drugs, new platinum(IV) prodrugs with desired chemical and biological properties can be subsequently obtained.…”

Section: Introductionmentioning

confidence: 99%

Ligand substitution reactions afford oxaliplatin-based platinum(iv) complexes bearing axial alkoxido ligands

Xu,

Lin,

et al. 2023

Inorg. Chem. Front.

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Platinum binding preferences dominate the binding of novel polyamide amidine anthraquinone platinum(ii) complexes to DNA

Abstract: Platinum(ii) complexes with a threading anthraquinone intercalator and a pyrrole lexitropsin have DNA profiles surprisingly similar to that of cisplatin suggesting the platinum binding dominates the sequence selectivity.

Cited by 2 publications

References 33 publications

Mechanistic study of dual‐function inhibitors targeting topoisomerase II and Rad51‐mediated DNA repair pathway against castration‐resistant prostate cancer

Mechanistic study of dual‐function inhibitors targeting topoisomerase II and Rad51‐mediated DNA repair pathway against castration‐resistant prostate cancer

Ligand substitution reactions afford oxaliplatin-based platinum(iv) complexes bearing axial alkoxido ligands

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