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Review
. 2024 Feb 6;29(4):746.
doi: 10.3390/molecules29040746.

Current Status of Novel Multifunctional Targeted Pt(IV) Compounds and Their Reductive Release Properties

Affiliations
Review

Current Status of Novel Multifunctional Targeted Pt(IV) Compounds and Their Reductive Release Properties

Lingwen Xu et al. Molecules. .

Abstract

Platinum-based drugs are widely used in chemotherapy for various types of cancer and are considered crucial. Tetravalent platinum (Pt(IV)) compounds have gained significant attention and have been extensively researched among these drugs. Traditionally, Pt(IV) compounds are reduced to divalent platinum (Pt(II)) after entering cells, causing DNA lesions and exhibiting their anti-tumor effect. However, the available evidence indicates that some Pt(IV) derivatives may differ from the traditional mechanism and exert their anti-tumor effect through their overall structure. This review primarily focuses on the existing literature regarding targeted Pt(II) and Pt(IV) compounds, with a specific emphasis on their in vivo mode of action and the properties of reduction release in multifunctional Pt(IV) compounds. This review provides a comprehensive summary of the design and synthesis strategies employed for Pt(II) derivatives that selectively target various enzymes (glucose receptor, folate, telomerase, etc.) or substances (mitochondria, oleic acid, etc.). Furthermore, it thoroughly examines and summarizes the rational design, anti-tumor mechanism of action, and reductive release capacity of novel multifunctional Pt(IV) compounds, such as those targeting p53-MDM2, COX-2, lipid metabolism, dual drugs, and drug delivery systems. Finally, this review aims to provide theoretical support for the rational design and development of new targeted Pt(IV) compounds.

Keywords: anti-tumor; divalent platinum; multifunctional targeted; reductive release; tetravalent platinum.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Chemical structures of classical platinum-based drugs.
Figure 2
Figure 2
Flowchart of the mechanism of anti-tumor action of cisplatin and oxaliplatin as an example. The green shadow is the leaving groups.
Figure 3
Figure 3
Chemical structures of novel targeting Pt(II) compounds. Red font represents core platinum atoms.
Scheme 1
Scheme 1
Synthesis route of PIP-platin. (Reprinted with permission from Ref. [57]. Copyright 2017 The Royal Society of Chemistry). Nitrogen atoms are shown in blue, platinum atoms are shown in red, and phosphorus atom is shown in green.
Scheme 2
Scheme 2
The synthetic routes of Λ-RuPt and Δ-RuPt. Reagents: (a) pyridine, MeOH, H2O, reflux; (b) disodium (-)-O,O’-dibenzoyl-LL-tartrate; (c) (i) 1,10-phenanthroline-5,6-dione, ethylene glycol–H2O (9:1), 120 °C, (ii) NaClO4; H2O; (d) 1,10-phenanthroline-2-carboxamide hydrazone, CH3CN/EtOH (3:1), alumina/CH3CN. (Reprinted with permission from Ref. [59]. Copyright 2002 Elsevier). (e) Pt(DMSO)2Cl2, MeCN/EtOH, reflux. (Reprinted with permission from Ref. [60]. Copyright 2022 Wiley). Red shading represents ruthenium atoms.
Figure 4
Figure 4
Taking cisplatin as an example, there are changes in the spatial structure of Pt(II) and Pt(IV) compounds.
Figure 5
Figure 5
Flowchart of the mechanism of anti-tumor action of Pt(IV) compounds. The blue R1 or R2 font is the substituent group and the red font represents the interstrand cross-linking (ICL).
Figure 6
Figure 6
Cellular entry pathways and reduction processes of cisplatin, monochalcoplatin, and chalcoplatin. (Reprinted with permission from Ref. [68]. Copyright 2018 Wiley).
Figure 7
Figure 7
(A) Chemical structures of DNP and NP. (B) 195Pt-NMR spectroscopy for determining the amount of Pt(II) released by the reduction of NP and DNP under ASA incubation; (C) DNP’s putative anti-cancer mechanism. (Reprinted with permission from Ref. [37]. Copyright 2020 Wiley).
Figure 8
Figure 8
(A) The intracellular release of Pt(II) after incubation of compound 10 (100 μM) in MCF-7 cells at different times was determined by HPLC. (Reprinted with permission from Ref. [74]. Copyright 2023 American Chemical Society). (B) The intracellular release of Pt(II) after incubation of compound 14 (100 μM) in MCF-7 cells for different times was determined by HPLC. (Reprinted with permission from Ref. [75]. Copyright 2019 American Chemical Society).
Figure 9
Figure 9
(A) Chemical structure of Pt(IV)-Sal. (B) Mechanisms for reducing Pt(IV) complexes by AsA and Cys in the inner sphere. (Reprinted with permission from Ref. [76]. Copyright 2022 MDPI). (C) Synthesis route of Pt(IV)-cross-linked nanogels and the delivery mechanism of action of the complexes. (D) Pt(II) release from Pt(IV) after in vitro incubation with different reducing agents (Reprinted with permission from Ref. [19]. Copyright 2021 Elsevier).
Figure 10
Figure 10
(A) Chemical structure of compound 4. (B) (a) The expression of PARP-1 was measured at different compounds. (b) Inhibition of PARP-1 expression was tested by administering compound 4 at different concentrations. (Reprinted with permission from Ref. [90]. Copyright 2017 Elsevier). All rights reserved. (C) Chemical structures of mitochondria-targeting bifunctional Pt(IV) pro-drugs. (D) The mechanism of action diagram of 3cis. (Reprinted with permission from Ref. [91]. Copyright 2019 Wiley).

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References

    1. Khoury A., Deo K.M., Aldrich-Wright J.R. Recent advances in platinum-based chemotherapeutics that exhibit inhibitory and targeted mechanisms of action. J. Inorg. Biochem. 2020;207:111070. doi: 10.1016/j.jinorgbio.2020.111070. - DOI - PubMed
    1. Pan Z., Zheng J., Zhang J., Lin J., Lai J., Lyu Z., Feng H., Wang J., Wu D., Li Y. A Novel Protein Encoded by Exosomal CircATG4B Induces Oxaliplatin Resistance in Colorectal Cancer by Promoting Autophagy. Adv. Sci. 2022;9:2204513. doi: 10.1002/advs.202204513. - DOI - PMC - PubMed
    1. Wilson J.J., Lippard S.J. Synthetic Methods for the Preparation of Platinum Anti-cancer Complexes. Chem. Rev. 2013;114:4470–4495. doi: 10.1021/cr4004314. - DOI - PMC - PubMed
    1. Johnstone T.C., Suntharalingam K., Lippard S.J. The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Pro-drugs. Chem. Rev. 2016;116:3436–3486. doi: 10.1021/acs.chemrev.5b00597. - DOI - PMC - PubMed
    1. da Costa A.A.B.A., Baiocchi G. Genomic profiling of platinum-resistant ovarian cancer: The road into druggable targets. Semin. Cancer Biol. 2021;77:29–41. doi: 10.1016/j.semcancer.2020.10.016. - DOI - PubMed