Recent advances in the synthesis, stability, and activation of platinum(IV) anticancer prodrugs

Xu, Zoufeng; Wang, Zhigang; Deng, Zhiqin; Zhu, Guangyu

doi:10.1016/j.ccr.2021.213991

Cited by 118 publications

(107 citation statements)

References 205 publications

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“…A promising strategy employed to diminish the limitations associated with platinum(II) drugs is to develop new platinum(IV) complexes. Accordingly, a series of comprehensible reviews have highlighted the likelihood of platinum(IV) complexes as the future of platinum-based drugs in chemotherapy [ 26 , 27 , 28 , 29 , 30 , 31 ]. Platinum(IV) complexes have a six-coordinate octahedral geometry where the two axial positions allow the coordination of additional ligands in contrast with square planar geometry of platinum(II) complexes ( Figure 3 ) [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

“…Numerous examples of multi-action platinum(IV) prodrugs incorporating bioactive axial ligands that target or inhibit polypeptides and enzymes have been reported in the literature [ 28 , 30 , 37 ]. However, research into the conjugation of a DNA-alkylating drug such as 4-[ bis (2-chloroethyl)amino] phenylbutyric acid (brand name: Leukeran, or chlorambucil (CLB)) as an axial ligand to platinum is limited.…”

Section: Introductionmentioning

confidence: 99%

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Potent Chlorambucil-Platinum(IV) Prodrugs

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Elias

Gilbert

et al. 2022

IJMS

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The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, [PtIV(HL)(AL)(OH)2](NO3)2 (where HL is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, PCLB, 5CLB, and 56CLB, 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, PHENSS, 5MESS, and 56MESS. Notably, 56CLB was exceptionally potent in HT29 colon, Du145 prostate, MCF10A breast, MIA pancreas, H460 lung, A2780, and ADDP ovarian cell lines, with GI50 values ranging between 2.7 and 21 nM. Moreover, significant production of reactive oxygen species was detected in HT29 cells after treatment with PCLB, 5CLB, and 56CLB up to 72 h compared to chlorambucil and the platinum(II) and (IV) precursors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potent Chlorambucil-Platinum(IV) Prodrugs

Aputen

Elias

Gilbert

et al. 2022

IJMS

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“…The complexes differ in the length of the [CH 2 ] n arm (n = 2 or 6) which links the carboxylate functionality anchored to the Pt(IV) core and the terminal 3-ABA moiety. An "innocent" (biologically inactive) acetato ligand was used for the second axial position of Pt(IV), with the aim of conferring higher stability with respect to reduction and hydrolysis than the chlorido ligand present in SAA1 [35,36].…”

Section: Synthesis Of the Bifunctional Pt(iv) Prodrugsmentioning

confidence: 99%

Unsymmetric Cisplatin-Based Pt(IV) Conjugates Containing a PARP-1 Inhibitor Pharmacophore Tested on Malignant Pleural Mesothelioma Cell Lines

et al. 2021

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Cisplatin is widely employed as a first-line chemotherapeutic agent for many solid tumors, including malignant pleural mesothelioma (MPM). However, its clinical use is limited by heavy side effects and acquired resistance, the latter being mainly related to enhanced DNA repair. Many clinical trials using combinations of platinum drugs and PARP-1 inhibitors (PARPis) have been carried out, with the hope that such combinations might lead to improved therapeutic efficacy against tumors. Here, the synthesis and efficacy in reducing MPM cell viability of four cisplatin-based Pt(IV) prodrugs containing the PARPi 3-aminobenzamide (3-ABA) fragment are described. The most promising conjugate is more effective than cisplatin or cisplatin/3-ABA combination, administered in equimolar doses, in inhibiting PARP-1 activity and inducing apoptosis in BRCA1/2 wild type MPM cells, grown as monolayer or as multicellular spheroids.

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“…In recent years, a number of excellent reviews on the advances of photoactivated anticancer Pt(IV) prodrugs have been published. They focused on various aspects of this unique family of prodrugs, for instance, synthesis ( Wilson and Lippard, 2014 ; Xu et al, 2021b ), phototherapy potency ( Gurruchaga-Pereda et al, 2019 ; Imberti et al, 2020 ), photoactivation mode and mechanism of action ( Dai and Wang, 2020 ; Xu et al, 2021b ), axial substitutions and modifications, and delivery ( Johnstone et al, 2016 ; Kenny and Marmion, 2019 ; Ravera et al, 2019 ; Jia et al, 2021 ) either in general view of Pt-based anticancer complexes ( Imran et al, 2018 ; Ravera et al, 2022 ) or in a specific view of a subgroup, for example, diazido-type Pt(IV) prodrugs ( Shi et al, 2019 ; Mu et al, 2021 ). However, few articles have presented a comprehensive summary and review on the evaluation of the coordinated ligands, namely, non-leaving ligands, leaving ligands, and axial ligands ( Wilson and Lippard, 2014 ), in photoactivated anticancer Pt(IV) prodrugs.…”

Section: Introductionmentioning

confidence: 99%

Ligand Evolution in the Photoactivatable Platinum(IV) Anticancer Prodrugs

et al. 2022

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Photoactivatable Pt(IV) anticancer prodrugs with the structure of [PtIV(N1)(N2)(L1)(L2)(A1)(A2)], where N1 and N2 are non-leaving nitrogen donor ligands, L1 and L2 are leaving ligands, and A1 and A2 are axial ligands, have attracted increasing attention due to their promising photo-cytotoxicity even to cisplatin-resistant cancer cells. These photochemotherapeutic prodrugs have high dark-stability under physiological conditions, while they can be activated by visible light restrained at the disease areas, as a consequence showing higher spatial and temporal controllability and much more safety than conventional chemotherapy. The coordinated ligands to the Pt center have been proved to be pivotal in determining the function and activity of the photoactivatable Pt(IV) prodrugs. In this review, we will focus on the development of the coordinated ligands in such Pt(IV) prodrugs and discuss the effects of diverse ligands on their photochemistry and photoactivity as well as the future evolution directions of the ligands. We hope this review can help to facilitate the design and development of novel photoactivatable Pt(IV) anticancer prodrugs.

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Recent advances in the synthesis, stability, and activation of platinum(IV) anticancer prodrugs

Cited by 118 publications

References 205 publications

Potent Chlorambucil-Platinum(IV) Prodrugs

Potent Chlorambucil-Platinum(IV) Prodrugs

Unsymmetric Cisplatin-Based Pt(IV) Conjugates Containing a PARP-1 Inhibitor Pharmacophore Tested on Malignant Pleural Mesothelioma Cell Lines

Ligand Evolution in the Photoactivatable Platinum(IV) Anticancer Prodrugs

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