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1.
Photochem Photobiol Sci ; 23(9): 1757-1769, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39242437

ABSTRACT

Porphyrazines (Pzs) are porphyrin derivatives that show potential application as photosensitizers for photodynamic therapy (PDT), but are still far less explored in the literature. In this work, we evaluate how the photophysics and phototoxicity of the octakis(trifluoromethylphenyl)porphyrazine (H2Pz) against tumor cells can be modulated by coordination with Mg(II), Zn(II), Cu(II) and Co(II) ions. Fluorescence and singlet oxygen quantum yields for the Pzs were measured in organic solvents and in soy phosphatidylcholine (PC) liposomes suspended in water. While H2Pz and the respective complexes with Cu(II) and Co(II) showed very low efficiency to fluoresce and to produce 1O2, the Mg(II) and Zn(II) complexes showed significantly higher quantum yields in organic solvents. The fluorescence of these two Pzs in the liposomes was sensitive to the fluidity of the membrane, showing potential use as viscosity markers. The cytotoxicity of the compounds was tested in HaCaT (normal) and A431 (tumor) cells using soy PC liposomes as drug carriers. Despite the low 1O2 quantum yields in water, the Mg(II) and Zn(II) complexes showed IC50 values against A431 cells in the nanomolar range when activated with low doses of red LED light. Their phototoxicity was ca. three times higher for the tumor cells compared to the normal ones, showing promising application as photosensitizers for PDT protocols. Considering that H2Pz and the respective Co(II) and Cu(II) complexes were practically non-phototoxic to the cells, we demonstrate the importance of the central metal ion in the modulation of the photodynamic activity of porphyrazines.


Subject(s)
Liposomes , Photosensitizing Agents , Porphyrins , Humans , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Porphyrins/chemistry , Porphyrins/pharmacology , Liposomes/chemistry , Photochemotherapy , Singlet Oxygen/metabolism , Singlet Oxygen/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Zinc/chemistry , Zinc/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Ions/chemistry
2.
Int J Mol Sci ; 25(16)2024 Aug 13.
Article in English | MEDLINE | ID: mdl-39201489

ABSTRACT

Triple-negative breast cancer (TNBC), accounting for 15-20% of all breast cancers, has one of the poorest prognoses and survival rates. Metastasis, a critical process in cancer progression, causes most cancer-related deaths, underscoring the need for alternative therapeutic approaches. This study explores the anti-migratory, anti-invasive, anti-tumoral, and antimetastatic effects of copper coordination compounds Casiopeína IIIia (CasIIIia) and Casiopeína IIgly (CasIIgly) on MDA-MB-231 and 4T1 breast carcinoma cell lines in vitro and in vivo. These emerging anticancer agents, mixed chelate copper(II) compounds, induce apoptosis by generating reactive oxygen species (ROS) and causing DNA damage. Whole-transcriptome analysis via gene expression arrays indicated that subtoxic concentrations of CasIIIia upregulate genes involved in metal response mechanisms. Casiopeínas® reduced TNBC cell viability dose-dependently and more efficiently than Cisplatin. At subtoxic concentrations (IC20), they inhibited random and chemotactic migration of MDA-MB-231 and 4T1 cells by 50-60%, similar to Cisplatin, as confirmed by transcriptome analysis. In vivo, CasIIIia and Cisplatin significantly reduced tumor growth, volume, and weight in a syngeneic breast cancer model with 4T1 cells. Furthermore, both compounds significantly decreased metastatic foci in treated mice compared to controls. Thus, CasIIIia and CasIIgly are promising chemotherapeutic candidates against TNBC.


Subject(s)
Antineoplastic Agents , Copper , Triple Negative Breast Neoplasms , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Animals , Humans , Female , Copper/chemistry , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Chelating Agents/pharmacology , Apoptosis/drug effects , Xenograft Model Antitumor Assays , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/therapeutic use , Cell Movement/drug effects , Reactive Oxygen Species/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Mice, Inbred BALB C , DNA Damage/drug effects
4.
Inorg Chem ; 63(37): 17087-17099, 2024 Sep 16.
Article in English | MEDLINE | ID: mdl-39185932

ABSTRACT

To ascertain the bioinorganic chemistry of metals conjugated with quinones, the complexes [Ag(ATV)(PPh3)2] (1), [Au(ATV)(PPh3)]·2H2O (2), and [Cu(ATV)(PPh3)2] (3) were synthesized by the coordination of the antimalarial naphthoquinone atovaquone (ATV) to the starting materials [Ag(PPh3)2]NO3, [Au(PPh3)Cl], and [Cu(PPh3)2NO3], respectively. These complexes were characterized by analytical and spectroscopical techniques. X-ray diffraction of single crystals precisely confirmed the coordination mode of ATV to the metals, which was monodentate or bidentate, depending on the metal center. Both coordination modes showed high stability in the solid state and in solution. All three complexes showed negative log D values at pH 5, but at pH 7.4, while complex 2 continued to have a negative log D value, complexes 1 and 3 displayed positive values, indicating a more hydrophilic character. ATV and complexes 1-3 could bind to ferriprotoporphyrin IX (FePPIX); however, only complexes 1-3 could inhibit ß-hematin crystal formation. Phenotype-based activity revealed that all three metal complexes are able to inhibit the growth of P. falciparum with potency and selectivity comparable to those of ATV, while the starting materials lack this activity. The outcomes of this chemical design may provide significant insights into structure-activity relationships for the development of new antimalarial agents.


Subject(s)
Antimalarials , Atovaquone , Coordination Complexes , Heme , Plasmodium falciparum , Antimalarials/pharmacology , Antimalarials/chemistry , Antimalarials/chemical synthesis , Plasmodium falciparum/drug effects , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Heme/chemistry , Atovaquone/pharmacology , Atovaquone/chemistry , Atovaquone/chemical synthesis , Molecular Structure , Copper/chemistry , Copper/pharmacology , Silver/chemistry , Silver/pharmacology , Gold/chemistry , Gold/pharmacology , Phosphines/chemistry , Phosphines/pharmacology , Parasitic Sensitivity Tests , Structure-Activity Relationship , Models, Molecular , Humans
5.
J Inorg Biochem ; 260: 112700, 2024 Nov.
Article in English | MEDLINE | ID: mdl-39163715

ABSTRACT

The success of a classic inorganic coordination compound, Cisplatin, cis-[Pt(NH3)2Cl2], as the first anticancer metallodrug started a field of research dedicated to discovering coordination compounds with antitumor activity, encompassing various metals. Among these, copper complexes have emerged as interesting candidates to develop drugs to treat cancer. In this work, mixed ligand complexes of Cu(II) with diimines (phenanthroline or 4-methylphenanthroline) and 3-(4-hydroxyphenyl)propanoate, phenylcarboxylate or phenylacetate were synthesized. They were characterized in the solid state, including a new crystal structure of [Cu2(3-(4-hydroxyphenyl)propanoate)3(phenanthroline)2]Cl·H2O. The obtained complexes presented a variety of stoichiometries. In solution, complexes were partially dissociated in the corresponding Cu-diimine complex. The complexes bound to the DNA by partial intercalation and groove binding, as assessed by Circular Dichroism, relative viscosity change and UV-Vis titration. The cytotoxicity of the complexes was determined in vitro on MDA-MB-231, MCF-7 (human metastatic breast adenocarcinomas, the first triple negative), MCF-10A (breast nontumoral), A549 (human lung epithelial carcinoma), and MRC-5 (human nontumoral lung epithelial cells), finding an activity higher than that of Cisplatin, although with less selectivity.


Subject(s)
Antineoplastic Agents , Coordination Complexes , Copper , Phenanthrolines , Humans , Copper/chemistry , Phenanthrolines/chemistry , Phenanthrolines/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Cell Line, Tumor , Ligands , DNA/chemistry , DNA/metabolism , A549 Cells , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Neoplasms/drug therapy , Neoplasms/metabolism , MCF-7 Cells
6.
Inorg Chem ; 63(31): 14673-14690, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-39042379

ABSTRACT

Metallocompounds have emerged as promising new anticancer agents, which can also exhibit properties to be used in photodynamic therapy. Here, we prepared two ruthenium-based compounds with a 2,2'-bipyridine ligand conjugated to an anthracenyl moiety. These compounds coded GRBA and GRPA contain 2,2'-bipyridine or 1,10-phenathroline as auxiliary ligands, respectively, which provide quite a distinct behavior. Notably, compound GRPA exhibited remarkably high photoproduction of singlet oxygen even in water (Ï•Δ = 0.96), almost twice that of GRBA (Ï•Δ = 0.52). On the other hand, this latter produced twice more superoxide and hydroxyl radical species than GRPA, which may be due to the modulation of their excited state. Interestingly, GRPA exhibited a modest binding to DNA (Kb = 4.51 × 104), while GRBA did not show a measurable interaction only noticed by circular dichroism measurements. Studies with bacteria showed a great antimicrobial effect, including a synergistic effect in combination with commercial antibiotics. Besides that, GRBA showed very low or no cytotoxicity against four mammalian cells, including a hard-to-treat MDA-MB-231, triple-negative human breast cancer. Potent activities were measured for GRBA upon blue light irradiation, where IC50 of 43 and 13 nmol L-1 were seen against hard-to-treat triple-negative human breast cancer (MDA-MB-231) and ovarian cancer cells (A2780), respectively. These promising results are an interesting case of a simple modification with expressive enhancement of biological activity that deserves further biological studies.


Subject(s)
Anti-Bacterial Agents , Antineoplastic Agents , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Molecular Structure , Microbial Sensitivity Tests , Drug Screening Assays, Antitumor , Ruthenium Compounds/pharmacology , Ruthenium Compounds/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Cell Line, Tumor , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/chemical synthesis , Ruthenium/chemistry , Ruthenium/pharmacology , Cell Proliferation/drug effects , Drug Resistance, Bacterial/drug effects , Photochemical Processes , Cell Survival/drug effects , Photochemotherapy
7.
Dalton Trans ; 53(30): 12567-12581, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-39005067

ABSTRACT

In this work, a polyhedral silsesquioxane (POSS) was used as an engineered drug delivery system for two oxindolimine-copper(II) anticancer complexes, [Cu(isaepy)]+ and [Cu(isapn)]+. The interest in hybrid POSS comes from the necessity of developing materials that can act as adjuvants to improve the cytotoxicity of non-soluble metallodrugs. Functionalization of POSS with a triazole ligand (POSS-atzac) permitted the anchorage of such copper complexes, producing hybrid materials with efficient cytotoxic effects. Structural and morphological characterizations of these copper-POSS systems were performed by using different techniques (IR, NMR, thermogravimetric analysis). A combination of continuous-wave (CW) and pulsed EPR (HYSCORE) spectroscopies conducted at the X-band have enabled the complete characterization of the coordination environment of the copper ion in the POSS-atzac matrix. Additionally, the cytotoxic effects of the loaded materials, [Cu(isapn)]@POSS-atzac and [Cu(isaepy)]@POSS-atzac, were assessed toward melanomas (SK-MEL), in comparison to non-tumorigenic cells (fibroblast P4). Evaluation of their nuclease activity or ability to facilitate cleavage of DNA indicated concentrations as low as 0.6 µg mL-1, while complete DNA fragmentation was observed at 25 µg mL-1. By using adequate scavengers, investigations on active intermediates responsible for their cytotoxicity were performed, both in the absence and in the presence of ascorbate as a reducing agent. Based on the observed selective cytotoxicity of these materials toward melanomas, investigations on the reactivity of these complexes and corresponding POSS-materials with melanin, a molecule that contributes to melanoma resistance to chemotherapy, were carried out. Results indicated the main role of the binuclear copper species, formed at the surface of the silica matrix, in the observed reactivity and selectivity of these copper-POSS systems.


Subject(s)
Antineoplastic Agents , Coordination Complexes , Copper , Melanoma , Organosilicon Compounds , Copper/chemistry , Copper/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Humans , Melanoma/drug therapy , Melanoma/pathology , Organosilicon Compounds/chemistry , Organosilicon Compounds/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Cell Line, Tumor , Drug Delivery Systems , Cell Survival/drug effects , Drug Carriers/chemistry , Drug Screening Assays, Antitumor
8.
Dalton Trans ; 53(30): 12627-12640, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-39011568

ABSTRACT

Antimicrobial resistance has become a global threat to human health, which is coupled with the lack of novel drugs. Metallocompounds have emerged as promising diverse scaffolds for the development of new antibiotics. Herein, we prepared some metal compounds mainly focusing on cis-[Ru(bpy)(dppz)(SO3)(NO)](PF6) (PR02, bpy = 2,2'-bipyridine, dppz = dipyrido[3,2-a:2',3'-c]phenazine), in which phenazinic and nitric oxide ligands along with sulfite conferred some key properties. This compound exhibited a redox potential for bound NO+/0 of -0.252 V (vs. Ag|AgCl) and a high pH for nitrosyl-nitro conversion of 9.16, making the nitrosyl ligand the major species. These compounds were still able to bind to DNA structures. Interestingly, reduced glutathione (GSH) was unable to promote significant NO/HNO release, an uncommon feature of many similar systems. However, this reducing agent was essential to generate superoxide radicals. Antimicrobial studies were carried out using six bacterial strains, where none or very low activity was observed for Gram-negative bacteria. However, PR02 and PR (cis-[Ru(bpy)(dppz)Cl2]) showed high antibacterial activity in some Gram-positive strains (MBC for S. aureus up to 4.9 µmol L-1), where the activity of PR02 was similar to or at least 4-fold better than that of PR. Besides, PR02 showed capacity to inhibit bacterial biofilm formation, a major health issue leading to bacterial tolerance to antibiotics. Interestingly, we also showed that PR02 can function in synergism with the known antibiotic ampicillin, improving their action up to 4-fold even against resistant strains. Altogether, these results showed that PR02 is a promising antimicrobial nitrosyl ruthenium compound combining features beyond its killing action, which deserves further biological studies.


Subject(s)
Anti-Bacterial Agents , Biofilms , Coordination Complexes , Microbial Sensitivity Tests , Phenazines , Ruthenium , Phenazines/chemistry , Phenazines/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Ruthenium/chemistry , Ruthenium/pharmacology , Biofilms/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Drug Synergism , Staphylococcus aureus/drug effects
9.
Inorg Chem ; 63(32): 14827-14850, 2024 Aug 12.
Article in English | MEDLINE | ID: mdl-39078252

ABSTRACT

We report the discovery that the molecule 1-(pyridin-2-ylmethylamino)propan-2-ol (HL) can reduce oxidative stress in neuronal C6 glioma cells exposed to reactive oxygen species (O2-•, H2O2, and •OH) and metal (Cu+) stress conditions. Furthermore, its association with Cu2+ generates [Cu(HL)Cl2] (1) and [Cu(HL)2](ClO4)2 (2) complexes that also exhibit antioxidant properties. Potentiometric titration data show that HL can coordinate to Cu2+ in 1:1 and 1:2 Cu2+:ligand ratios, which was confirmed by monocrystal X-ray studies. The subsequent ultraviolet-visible, electrospray ionization mass spectrometry, and electron paramagnetic resonance experiments show that they can decompose a variety of reactive oxygen species (ROS). Kinetic studies revealed that 1 and 2 mimic the superoxide dismutase and catalase activities. Complex 1 promotes the fastest decomposition of H2O2 (kobs = 2.32 × 107 M-1 s-1), efficiently dismutases the superoxide anion (kcat = 3.08 × 107 M-1 s-1), and scavenges the hydroxyl radical (RSA50 = 25.7 × 10-6 M). Density functional theory calculations support the formation of dinuclear Cu-peroxide and mononuclear Cu-superoxide species in the reactions of [Cu(HL)Cl2] with H2O2 and O2•-, respectively. Furthermore, both 1 and 2 also reduce the oxidative stress of neuronal glioma C6 cells exposed to different ROS, including O2•- and •OH.


Subject(s)
Antioxidants , Coordination Complexes , Copper , Oxidative Stress , Copper/chemistry , Copper/pharmacology , Oxidative Stress/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Antioxidants/pharmacology , Antioxidants/chemistry , Antioxidants/chemical synthesis , Density Functional Theory , Reactive Oxygen Species/metabolism , Catalysis , Animals , Molecular Structure , Cell Line, Tumor , Rats , Humans
10.
Drug Discov Today ; 29(9): 104100, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39019429

ABSTRACT

Metallocompounds are a class of anticancer compounds largely used in the treatment of several types of solid tumors, including bone cancer. Osteosarcoma (OS) is a primary malignant bone tumor that frequently affects children, adolescents and young adults. It is a very invasive type of tumor, so ∼40% of patients develop distant metastases, showing elevated mortality rates. In this review, we present an outline of the chemistry and antitumor properties of metal-based compounds in preclinical (in vitro and in vivo) and clinical OS models, focusing on the relationship between structure-activity, molecular targets and the study of the mechanism of action involved in metallocompound anticancer activity.


Subject(s)
Antineoplastic Agents , Bone Neoplasms , Osteosarcoma , Osteosarcoma/drug therapy , Osteosarcoma/pathology , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Animals , Structure-Activity Relationship , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic use , Coordination Complexes/chemistry
11.
J Biol Inorg Chem ; 29(5): 519-529, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39009790

ABSTRACT

Lapachol (2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione) is a 1,4-naphthoquinone-derived natural product that presents numerous bioactivities and was shown to have cytotoxic effects against several human tumor cells. Indium(III) complexes with a variety of ligands also exhibit antineoplastic activity. Indium(III) complexes [In(lap)Cl2].4H2O (1), [In(lap)2Cl(Et3N)] (2), [In(lap)3]·2H2O (3) [In(lap)(bipy)Cl2] bipy = 2,2'-bipyridine (4) and [In(lap)(phen)Cl2] phen = 1,10-phenanthroline (5) were obtained with 2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione (lapachol). Crystal structure determinations for (4) and (5) revealed that the indium(III) center is coordinated to two O atoms from lapachol, two N atoms from 1,10-phenanthroline or 2,2'-bipyridine, and two chloride anions, in a distorted octahedral geometry. Although both complexes (4) and (5) interacted with CT-DNA in vitro by an intercalative mode, only 5 exhibited cytotoxicity against MCF-7 and MDA-MB breast tumor cells. 1,10-phenanthroline and complex (5) presented cytotoxic effects against MCF-7 and MDA-MB cells, with complex (5) being threefold more active than 1,10-phenanthroline on MCF-7 cells. In addition, complex (5) significantly reduced the formation of MDA-MB-231 colonies in a clonogenicity assay. The foregoing results suggest that further studies on the cytotoxic effects and cellular targets of complex (5) are of utmost relevance.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , DNA , Indium , Naphthoquinones , Humans , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Indium/chemistry , Indium/pharmacology , DNA/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Cell Line, Tumor , Female , Drug Screening Assays, Antitumor , Crystallography, X-Ray , MCF-7 Cells , Models, Molecular , Molecular Structure
12.
Biomed Pharmacother ; 177: 117059, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38955086

ABSTRACT

Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF6, to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs.


Subject(s)
Apoptosis , Autophagic Cell Death , Liver Neoplasms , Neoplastic Stem Cells , Proto-Oncogene Proteins c-akt , Signal Transduction , TOR Serine-Threonine Kinases , Humans , Apoptosis/drug effects , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Signal Transduction/drug effects , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Hep G2 Cells , Autophagic Cell Death/drug effects , Thiazolidines/pharmacology , Animals , Mice , Cell Movement/drug effects , Antineoplastic Agents/pharmacology , Autophagy/drug effects , Coordination Complexes/pharmacology , Coordination Complexes/chemistry
13.
Inorg Chem ; 63(25): 11667-11687, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38860314

ABSTRACT

Human African trypanosomiasis (HAT, sleeping sickness) and American trypanosomiasis (Chagas disease) are endemic zoonotic diseases caused by genomically related trypanosomatid protozoan parasites (Trypanosoma brucei and Trypanosoma cruzi, respectively). Just a few old drugs are available for their treatment, with most of them sharing poor safety, efficacy, and pharmacokinetic profiles. Only fexinidazole has been recently incorporated into the arsenal for the treatment of HAT. In this work, new multifunctional Ru(II) ferrocenyl compounds were rationally designed as potential agents against these pathogens by including in a single molecule 1,1'-bis(diphenylphosphino)ferrocene (dppf) and two bioactive bidentate ligands: pyridine-2-thiolato-1-oxide ligand (mpo) and polypyridyl ligands (NN). Three [Ru(mpo)(dppf)(NN)](PF6) compounds and their derivatives with chloride as a counterion were synthesized and fully characterized in solid state and solution. They showed in vitro activity on bloodstream T. brucei (EC50 = 31-160 nM) and on T. cruzi trypomastigotes (EC50 = 190-410 nM). Compounds showed the lowest EC50 values on T. brucei when compared to the whole set of metal-based compounds previously developed by us. In addition, several of the Ru compounds showed good selectivity toward the parasites, particularly against the highly proliferative bloodstream form of T. brucei. Interaction with DNA and generation of reactive oxygen species (ROS) were ruled out as potential targets and modes of action of the Ru compounds. Biochemical assays and in silico analysis led to the insight that they are able to inhibit the NADH-dependent fumarate reductase from T. cruzi. One representative hit induced a mild oxidation of low molecular weight thiols in T. brucei. The compounds were stable for at least 72 h in two different media and more lipophilic than both bioactive ligands, mpo and NN. An initial assessment of the therapeutic efficacy of one of the most potent and selective candidates, [Ru(mpo)(dppf)(bipy)]Cl, was performed using a murine infection model of acute African trypanosomiasis. This hit compound lacks acute toxicity when applied to animals in the dose/regimen described, but was unable to control parasite proliferation in vivo, probably because of its rapid clearance or low biodistribution in the extracellular fluids. Future studies should investigate the pharmacokinetics of this compound in vivo and involve further research to gain deeper insight into the mechanism of action of the compounds.


Subject(s)
Ferrous Compounds , Ruthenium , Trypanocidal Agents , Trypanosoma cruzi , Ferrous Compounds/chemistry , Ferrous Compounds/pharmacology , Ferrous Compounds/chemical synthesis , Trypanosoma cruzi/drug effects , Ligands , Trypanocidal Agents/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/chemical synthesis , Animals , Ruthenium/chemistry , Ruthenium/pharmacology , Mice , Metallocenes/chemistry , Metallocenes/pharmacology , Metallocenes/chemical synthesis , Trypanosoma brucei brucei/drug effects , Parasitic Sensitivity Tests , Molecular Structure , Organometallic Compounds/pharmacology , Organometallic Compounds/chemistry , Organometallic Compounds/chemical synthesis , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis
14.
Molecules ; 29(12)2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38930825

ABSTRACT

The current article reports the investigation of three new Ni(II) complexes with ONS-donor dithiocarbazate ligands: [Ni(L1)PPh3] (1), [Ni(L2)PPh3] (2), and [Ni(L2)Py] (3). Single-crystal X-ray analyses revealed mononuclear complexes with a distorted square planar geometry and the metal centers coordinated with a doubly deprotonated dithiocarbazate ligand and coligand pyridine or triphenylphosphine. The non-covalent interactions were investigated by the Hirshfeld surface and the results revealed that the strongest interactions were π⋅⋅⋅π stacking interactions and non-classical hydrogen bonds C-H···H and C-H···N. Physicochemical and spectroscopic methods indicate the same structures in the solid state and solution. The toxicity effects of the free ligands and Ni(II) complexes were tested on the human breast cancer cell line MCF-7 and non-malignant breast epithelial cell line MCF-10A. The half-maximal inhibitory concentration (IC50) values, indicating that the compounds were potent in inhibiting cell growth, were obtained for both cell lines at three distinct time points. While inhibitory effects were evident in both malignant and non-malignant cells, all three complexes demonstrated lower IC50 values for malignant breast cell lines than their non-malignant counterparts, suggesting a stronger impact on cancerous cell lines. Furthermore, molecular docking studies were performed showing the complex (2) as a promising candidate for further therapeutic exploration.


Subject(s)
Antineoplastic Agents , Coordination Complexes , Molecular Docking Simulation , Nickel , Humans , Nickel/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Ligands , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Cell Line, Tumor , Crystallography, X-Ray , MCF-7 Cells , Molecular Structure , Cell Proliferation/drug effects , Drug Design
15.
Dalton Trans ; 53(26): 10947-10960, 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-38895770

ABSTRACT

The search for new metal-based anticancer drug candidates is a fundamental task in medicinal inorganic chemistry. In this work, we assessed the potential of two new Ru(II)-phosphine-mercapto complexes as potential anticancer agents. The complexes, with the formula [Ru(bipy)(dppen)(Lx)]PF6 [(1), HL1 = 2-mercapto-pyridine and (2), HL2 = 2-mercapto-pyrimidine, bipy = 2,2'-bipyridine, dppen = cis-1,2-bis(diphenylphosphino)-ethylene] were synthesized and characterized by nuclear magnetic resonance (NMR) [1H, 31P(1H), and 13C], high resolution mass spectrometry (HR-MS), cyclic voltammetry, infrared and UV-Vis spectroscopies. Complex 2 was obtained as a mixture of two isomers, 2a and 2b, respectively. The composition of these metal complexes was confirmed by elemental analysis and liquid chromatography-mass spectrometry (LC-MS). To obtain insights into their lipophilicity, their distribution coefficients between n-octanol/PBS were determined. Both complexes showed affinity mainly for the organic phase, presenting positive log P values. Also, their stability was confirmed over 48 h in different media (i.e., DMSO, PBS and cell culture medium) via HPLC, UV-Vis and 31P{1H} NMR spectroscopies. Since enzymes from the P-450 system play a crucial role in cellular detoxification and metabolism, the microsomal stability of 1, which was found to be the most interesting compound of this study, was investigated using human microsomes to verify its potential oxidation in the liver. The analyses by LC-MS and ESI-MS reveal three main metabolites, obtained by oxidation in the dppen and bipy moieties. Moreover, 1 was able to interact with human serum albumin (HSA). The cytotoxicity of the metal complexes was tested in different cancerous and non-cancerous cell lines. Complex 1 was found to be more selective than cisplatin against MDA-MB-231 breast cancer cells when compared to MCF-10A non-cancerous cells. In addition, complex 1 affects cell morphology and migration, and inhibits colony formation in MDA-MB-231 cells, making it a promising cytotoxic agent against breast cancer.


Subject(s)
Antineoplastic Agents , Coordination Complexes , Phosphines , Ruthenium , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Phosphines/chemistry , Phosphines/pharmacology , Ruthenium/chemistry , Ruthenium/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Cell Line, Tumor , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacology , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Molecular Structure
16.
Dalton Trans ; 53(31): 12951-12961, 2024 Aug 06.
Article in English | MEDLINE | ID: mdl-38842058

ABSTRACT

Four new copper(II) complexes were synthesized and characterized with the general formula [Cu(N-N)(Th)(NO3)], where N-N corresponds to the N-heterocyclic ligands 1,10-phenanthroline (phen), 2,2'-bipyridine (bipy), 4,7-diphenyl-1,10-phenanthroline (dpp), and 4,4-dimethyl-2,2'-bipyridine (dmbp) and Th represents the N,N-dibenzyl-N'-benzoylthiourea. Cytotoxic activities of the complexes against HCT116 (human colon carcinoma), HepG2 (human hepatocellular carcinoma), and non-tumor MRC-5 (human lung fibroblast) cells were investigated. The copper(II) complexes 1-4 were characterized by spectroscopic techniques while complexes 1 and 2 were studied using single-crystal X-ray diffraction as well. The complexes possessed a five-coordinated structure with one nitrate ligand as a monodentate at the axial position and two bidentate ligands N-heterocyclic and N,N-dibenzyl-N'-benzoylthiourea. The complexes showed promising IC50 values, ranging from 0.3 to 9.0 µM. Furthermore, interaction studies with biomolecules such as calf thymus DNA (ct-DNA) and Bovine Serum Albumin (BSA), which can act as possible biological targets of the complexes, were carried out. The studies suggested that the compounds interact moderately with ct-DNA and BSA. Complexes 1, 2, and 4 did not lead to cell accumulation at any stage of the cell cycle but caused a significant increase in internucleosomal DNA fragmentation. Whereas, compound 3 caused cell cycle arrest in the S phase while doxorubicin caused cell cycle arrest in the G2/M phase. The effect of structural modifications on the metal compounds was correlated with their biological properties and it was concluded that an increase in biological activity occurred with increasing the extension of the diimine ligands. Thus, complex 3 was the most promising one.


Subject(s)
Antineoplastic Agents , Cell Cycle , Coordination Complexes , Copper , DNA , Serum Albumin, Bovine , Thiourea , Copper/chemistry , Copper/pharmacology , Humans , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/metabolism , DNA/metabolism , DNA/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Cattle , Thiourea/chemistry , Thiourea/pharmacology , Cell Cycle/drug effects , Animals , Imines/chemistry , Imines/pharmacology , Drug Screening Assays, Antitumor , Cell Proliferation/drug effects , Molecular Structure
17.
Int J Mol Sci ; 25(12)2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38928242

ABSTRACT

Drug resistance in infectious diseases developed by bacteria and fungi is an important issue since it is necessary to further develop novel compounds with biological activity that counteract this problem. In addition, new pharmaceutical compounds with lower secondary effects to treat cancer are needed. Coordination compounds appear to be accessible and promising alternatives aiming to overcome these problems. In this review, we summarize the recent literature on coordination compounds based on nitrobenzoic acid (NBA) as a ligand, its derivatives, and other nitro-containing ligands, which are widely employed owing to their versatility. Additionally, an analysis of crystallographic data is presented, unraveling the coordination preferences and the most effective crystallization methods to grow crystals of good quality. This underscores the significance of elucidating crystalline structures and utilizing computational calculations to deepen the comprehension of the electronic properties of coordination complexes.


Subject(s)
Coordination Complexes , Ligands , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Nitrobenzoates/chemistry , Nitrobenzoates/pharmacology , Humans , Crystallography, X-Ray/methods , Nitro Compounds/chemistry , Nitro Compounds/pharmacology
18.
Biometals ; 37(5): 1237-1253, 2024 Oct.
Article in English | MEDLINE | ID: mdl-38874822

ABSTRACT

Candida species undeniably rank as the most prevalent opportunistic human fungal pathogens worldwide, with Candida albicans as the predominant representative. However, the emergence of non-albicans Candida species (NACs) has marked a significant shift, accompanied by rising incidence rates and concerning trends of antifungal resistance. The search for new strategies to combat antifungal-resistant Candida strains is of paramount importance. Recently, our research group reported the anti-Candida activity of a coordination compound containing copper(II) complexed with theophylline (theo) and 1,10-phenanthroline (phen), known as "CTP" - Cu(theo)2phen(H2O).5H2O. In the present work, we investigated the mechanisms of action of CTP against six medically relevant, antifungal-resistant NACs, including C. auris, C. glabrata, C. haemulonii, C. krusei, C. parapsilosis and C. tropicalis. CTP demonstrated significant efficacy in inhibiting mitochondrial dehydrogenases, leading to heightened intracellular reactive oxygen species production. CTP treatment resulted in substantial damage to the plasma membrane, as evidenced by the passive incorporation of propidium iodide, and induced DNA fragmentation as revealed by the TUNEL assay. Scanning electron microscopy images of post-CTP treatment NACs further illustrated profound alterations in the fungal surface morphology, including invaginations, cavitations and lysis. These surface modifications significantly impacted the ability of Candida cells to adhere to a polystyrene surface and to form robust biofilm structures. Moreover, CTP was effective in disassembling mature biofilms formed by these NACs. In conclusion, CTP represents a promising avenue for the development of novel antifungals with innovative mechanisms of action against clinically relevant NACs that are resistant to antifungals commonly used in clinical settings.


Subject(s)
Antifungal Agents , Candida , Coordination Complexes , Copper , Drug Resistance, Fungal , Microbial Sensitivity Tests , Phenanthrolines , Theophylline , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/chemical synthesis , Phenanthrolines/pharmacology , Phenanthrolines/chemistry , Candida/drug effects , Copper/chemistry , Copper/pharmacology , Drug Resistance, Fungal/drug effects , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Theophylline/pharmacology , Theophylline/chemistry , Reactive Oxygen Species/metabolism , Humans
19.
J Mol Model ; 30(6): 177, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38775913

ABSTRACT

CONTEXT: Bismuth complexes with dithiocarbamate ligands have attracted attention because of their biological applications, such as antimicrobial, antileishmanial, and anticancer properties. These complexes have high cytotoxic activity against cancer cells, being more active than the standard drugs cisplatin, doxorubicin, and tamoxifen. In the present study, we investigated the ability of some DFT methods to reproduce the geometries and NMR spectra of the Bi(III) dithiocarbamate complexes, selected based on their proven antitumor activity. Our investigation revealed that the M06-L/def2-TZVP/ECP/CPCM method presented good accuracy in predicting geometries, while the TPSSh/def2-SVP/ECP/CPCM method proved effective in analyzing the 13C NMR spectra of these molecules. In general, all examined methods exhibited comparable performance in predicting 1H NMR signals. METHODS: Calculations were performed with the Gaussian 09 program using the def2-SVP and def2-TZVP basis sets, employing relativistic effective core potential (ECP) for Bi and using the CPCM solvent model. The exchange-correlation functionals BP86, PBE, OLYP, M06-L, B3LYP, B3LYP-D3, M06-2X, TPSSh, CAM-B3LYP, and ωB97XD were used in the study. Geometry optimizations were started from crystallographic structures available at the Cambridge Structural Database. The theoretical results were compared with experimental data using the mean root-mean-square deviation (RMSD), mean absolute deviations (MAD), and linear correlation coefficient (R2).


Subject(s)
Antineoplastic Agents , Density Functional Theory , Magnetic Resonance Spectroscopy , Thiocarbamates , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Thiocarbamates/chemistry , Magnetic Resonance Spectroscopy/methods , Bismuth/chemistry , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Models, Molecular , Humans
20.
J Inorg Biochem ; 257: 112600, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38759261

ABSTRACT

Rhenium complexes show great promise as anticancer drug candidates. Specifically, compounds with a Re(CO)3(NN)(py)+ core in their architecture have shown cytotoxicity equal to or greater than that of well-established anticancer drugs based on platinum or organic molecules. This study aimed to evaluate how the strength of the interaction between rhenium(I) tricarbonyl complexes fac-[Re(CO)3(NN)(py)]+, NN = 1,10-phenanthroline (phen), dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) or dipyrido[3,2-a:2'3'-c]phenazine (dppz) and biomolecules (protein, lipid and DNA) impacted the corresponding cytotoxic effect in cells. Results showed that fac-[Re(CO)3(dppz)(py)]+ has higher Log Po/w and binding constant (Kb) with biomolecules (protein, lipid and DNA) compared to complexes of fac-[Re(CO)3(phen)(py)]+ and fac-[Re(CO)3(dpq)(py)]+. As consequence, fac-[Re(CO)3(dppz)(py)]+ exhibited the highest cytotoxicity (IC50 = 8.5 µM for HeLa cells) for fac-[Re(CO)3(dppz)(py)]+ among the studied compounds (IC50 > 15 µM). This highest cytotoxicity of fac-[Re(CO)3(dppz)(py)]+ are probably related to its lipophilicity, higher permeation of the lipid bilayers of cells, and a more potent interaction of the dppz ligand with biomolecules (protein and DNA). Our findings open novel avenues for rational drug design and highlight the importance of considering the chemical structures of rhenium complexes that strongly interact with biomolecules (proteins, lipids, and DNA).


Subject(s)
Antineoplastic Agents , Coordination Complexes , DNA , Rhenium , Rhenium/chemistry , Humans , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , DNA/chemistry , DNA/metabolism , Phenanthrolines/chemistry , Phenanthrolines/pharmacology , Quinoxalines/chemistry , Quinoxalines/pharmacology , Phenazines/chemistry , Phenazines/pharmacology , Cell Line, Tumor , HeLa Cells
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