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Journal ArticleDOI

From medium to endoplasmic reticulum: Tracing anticancer phenolato titanium(IV) complex by 19F NMR detection.

15 May 2021-Journal of Inorganic Biochemistry (Elsevier)-Vol. 221, pp 111492-111492
TL;DR: In this paper, a fluoro-substituted derivative, FenolaTi, was employed for mechanistic analysis of the active species and its cellular target by quantitative 19F NMR detection to reveal its biodistribution and reactivity in extracellular and intracellular matrices.
About: This article is published in Journal of Inorganic Biochemistry.The article was published on 2021-05-15 and is currently open access. It has received 7 citations till now. The article focuses on the topics: Endoplasmic reticulum & Bovine serum albumin.
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Journal ArticleDOI
TL;DR: Utilizing organic ligands with limited stability under biological conditions, such as Schiff bases, enhances the tuning of the reactivities of the metal complexes under the conditions of intratumoral injections, however, nanocarrier formulations are likely to be required for the delivery of unstable metal complexes into the tumor.
Abstract: Injections of highly cytotoxic or immunomodulating drugs directly into the inoperable tumor is a procedure that is increasingly applied in the clinic and uses established Pt-based drugs. It is advantageous for less stable anticancer metal complexes that fail administration by the standard intravenous route. Such hydrophobic metal-containing complexes are rapidly taken up into cancer cells and cause cell death, while the release of their relatively non-toxic decomposition products into the blood has low systemic toxicity and, in some cases, may even be beneficial. This concept was recently proposed for V(V) complexes with hydrophobic organic ligands, but it can potentially be applied to other metal complexes, such as Ti(IV), Ga(III) and Ru(III) complexes, some of which were previously unsuccessful in human clinical trials when administered via intravenous injections. The potential beneficial effects include antidiabetic, neuroprotective and tissue-regenerating activities for V(V/IV); antimicrobial activities for Ga(III); and antimetastatic and potentially immunogenic activities for Ru(III). Utilizing organic ligands with limited stability under biological conditions, such as Schiff bases, further enhances the tuning of the reactivities of the metal complexes under the conditions of intratumoral injections. However, nanocarrier formulations are likely to be required for the delivery of unstable metal complexes into the tumor.

8 citations

Journal ArticleDOI
TL;DR: A new family of titanium(IV) complexes based on [ONON] diaminobis(phenolato) ligands with Me, Br, Cl, and F ortho substitutions was synthesized and characterized in this paper .
Abstract: A new family of titanium(IV) complexes based on [ONON] diaminobis(phenolato) ligands with Me, Br, Cl, and F ortho substitutions was synthesized and characterized. X-ray structures of three derivatives revealed homoleptic L2Ti-type compounds that exhibit an octahedral geometry without binding of the dangling amine unit. DFT calculations demonstrated that the preference of an L2Ti complex is not driven by solvent or ligand substitutions but rather by entropic effects. Except for the fluorinated derivative that was hydrolyzed immediately following water addition at room temperature and had the lowest biological activity of the series tested, all other complexes showed cytotoxic activity comparable to or higher than (up to 10-fold) that of cisplatin toward human ovarian A2780 and colon HT-29 cancer cell lines (IC50 values: 0.6–13 μM after incubation for 72 h). Activity was generally higher (up to 10-fold) toward the more sensitive ovarian line and similar for all active complexes, whereas differences were recorded toward the colon line that are attributed to bioavailability variations among the complexes analyzed. Particularly high hydrolytic stability was recorded for the brominated derivative with a t1/2 of 17 ± 1 days for ligand hydrolysis in 10% D2O at room temperature, relative to t1/2 of 56 ± 5 and 22 ± 6 h measured for the chlorinated and methylated derivatives, respectively. Altogether this series of compounds represent a promising family of anticancer agents, with the chlorinated derivative showing the best combination of stability, cytotoxicity, and bioavailability.

5 citations

Journal ArticleDOI
TL;DR: In this article , the binding of phenolaTi, a leading diaminobis(phenolato)bis(alkoxo) Ti(IV) anticancer complex, to serum proteins, and derived the binding constants and thermodynamic parameters.

2 citations

Journal ArticleDOI
TL;DR: In this paper , the authors investigated the downstream effects of this mode of action in two cancer cell lines: ovarian carcinoma A2780 and cervical adenocarcinoma HeLa, showing that ER-stress is the main cellular mechanism of phenolaTi, leading to hypoxia and mitochondrial ROS.

1 citations

Journal ArticleDOI
TL;DR: A series of five titanium(IV) complexes based on diaminobis(phenolato)-bis(alkoxo) ligands with different substitutions was synthesized and characterized in this paper .
Abstract: A new series of five titanium(IV) complexes based on diaminobis(phenolato)-bis(alkoxo) ligands with different substitutions was synthesized and characterized. All complexes were analyzed by X-ray crystallography, and all structures indicated C2 symmetrical octahedral compounds. All complexes exhibited enhanced solubility in aqueous media compared with the parent methylated derivative phenolaTi (up to 0.4 vs. 0.05 mg ml-1 of phenolaTi) due to halogen and alkoxo/hydroxo substitutions, with particularly enhanced water solubility for the methoxylated and hydroxylated derivatives. In particular, high hydrolytic stability was recorded for all derivatives, with the t½ for ligand hydrolysis of more than 8 days, as established by 1H NMR and HR-MS. All complexes were cytotoxic toward human ovarian A2780, colon HT-29, and cervical HeLa cancer cell lines (IC50 values in the range of 0.3-40 μM), with negligible activity toward non-cancerous MRC-5 cells. The halogenated compounds of this series exhibit the best combination of stability and activity, making them highly promising for anticancer applications.
References
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Journal Article
TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.

289,852 citations

Journal ArticleDOI
TL;DR: Preclinical and clinical investigations showed that the development of new metal agents with modes of action different from cisplatin is possible, and complexes with iron, cobalt, or gold central atoms have shown promising results in preclinical studies and compounds with titanium, ruthenium, or galliumcentral atoms have already been evaluated in phase I and phase II trials.
Abstract: The development of metal complexes with platinum central atoms such as cisplatin or carboplatin had an enormous impact on current cancer chemotherapy. However, the spectrum of cancers that can be treated with platinum agents is narrow and treatment efficacy suffers from side effects and resistance phenomena. These unresolved problems in platinum-based anti-cancer therapy have stimulated increased research efforts in the search for novel non platinum-containing metal species as cytostatic agents. Preclinical and clinical investigations showed that the development of new metal agents with modes of action different from cisplatin is possible. Thus, complexes with iron, cobalt, or gold central atoms have shown promising results in preclinical studies and compounds with titanium, ruthenium, or gallium central atoms have already been evaluated in phase I and phase II trials. This review covers some relevant examples of preclinical and clinical research on novel non platinum metal complexes.

512 citations

Journal ArticleDOI
TL;DR: The intracellular localization of albumin was assessed in order to understand the mechanisms and pathways responsible for its uptake, distribution and catabolism in multiple tissues, and this is reviewed herein.
Abstract: Serum albumin is a multi-functional protein that is able to bind and transport numerous endogenous and exogenous compounds. The development of albumin drug carriers is gaining increasing importance in the targeted delivery of cancer therapy, particularly as a result of the market approval of the paclitaxel-loaded albumin nanoparticle, Abraxane®. Considering this, there is renewed interest in isolating and characterizing albumin-binding proteins or receptors on the plasma membrane that are responsible for albumin uptake. Initially, the cellular uptake and intracellular localization of albumin was unknown due to the large confinement of the protein within the vascular and interstitial compartment of the body. Studies have since assessed the intracellular localization of albumin in order to understand the mechanisms and pathways responsible for its uptake, distribution and catabolism in multiple tissues, and this is reviewed herein.

475 citations