Metal‐Containing Pharmacophores in Molecularly Targeted Anticancer Therapies and Diagnostics

Yang, Mu; Bierbach, Ulrich

doi:10.1002/ejic.201601149

Cited by 19 publications

(8 citation statements)

References 87 publications

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“…Cationic trithiolato dinuclear ruthenium(II)-arene complexes represent promising scaffolds. Tethering a functional molecule (e.g., fluorophore, metabolite, drug) to a metal framework is one of the strategies used for tracking, directing, or modulating the biological activity of metal-based complexes [37][38][39]. In numerous cases, conjugation to organometallic moieties led to the enhanced biological activity of the parental drug [4,40].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antiparasitic Activity of New Conjugates—Organic Drugs Tethered to Trithiolato-Bridged Dinuclear Ruthenium(II)–Arene Complexes

et al. 2021

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Tethering known drugs to a metalorganic moiety is an efficient approach for modulating the anticancer, antibacterial, and antiparasitic activity of organometallic complexes. This study focused on the synthesis and evaluation of new dinuclear ruthenium(II)–arene compounds linked to several antimicrobial compounds such as dapsone, sulfamethoxazole, sulfadiazine, sulfadoxine, triclosan, metronidazole, ciprofloxacin, as well as menadione (a 1,4-naphtoquinone derivative). In a primary screen, 30 compounds (17 hybrid molecules, diruthenium intermediates, and antimicrobials) were assessed for in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) at 0.1 and 1 µM. In parallel, the cytotoxicity in noninfected host cells (human foreskin fibroblasts, HFF) was determined by an alamarBlue assay. When assessed at 1 µM, five compounds strongly impaired parasite proliferation by >90%, and HFF viability was retained at 50% or more, and they were further subjected to T. gondii β-gal dose-response studies. Two compounds, notably 11 and 13, amide and ester conjugates with sulfadoxine and metronidazole, exhibited low IC50 (half-maximal inhibitory concentration) values 0.063 and 0.152 µM, and low or intermediate impairment of HFF viability at 2.5 µM (83 and 64%). The nature of the anchored drug as well as that of the linking unit impacted the biological activity.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Antiparasitic Activity of New Conjugates—Organic Drugs Tethered to Trithiolato-Bridged Dinuclear Ruthenium(II)–Arene Complexes

et al. 2021

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“…Thus, inhibition of these proteins and their downstream signaling by small-molecule tyrosine kinase inhibitors is a viable methodology for treatment. During the past 2 decades, various metal complexes (Figure ) bearing organic-directing groups showed the efficient inhibition of a wide variety of kinases, viz., EGFR, cyclin-dependent kinase (CDK), glycogen synthase kinase 3 beta (GSK 3β), proto-oncogene serine/threonine protein kinase (Pim1), mitogen- and stress-activated protein kinase (MSK1), P21 (RAC1) activated kinase 1 (PAK1), macrophage stimulating 1 (MST1), and myosin light chain kinase (MLCK). ,− However, metal complexes that efficiently inhibit VEGFR2 phosphorylation are scarce. , The design of kinase targeting metal complexes benefits from a ligand that alone can target the ATP binding domain in the kinases, and such metal complexes involve the use of derivatives of clinically relevant motifs. ,, Benzimidazolyl and pyrazolyl compounds are known to be part of a wide variety of clinical drugs with excellent potency, encompassing nonsteroidal antiinflammatory drugs, alkylating agents, anthelmintics, and proton pump inhibitors. − In this work, we present halido-substituted 2-(1 H -pyrazol-1-yl)-1 H -benzo[ d ]imidazole bidentate ligands to design Ru II complexes that inhibit VEGFR2 phosphorylation. We have synthesized and characterized four ligands ( L1 – L4 ), providing eight Ru II complexes ( 1 – 8 ) with variation of a halide on the 4 position of the pyrazole in the bidentate ligand and in coordination to Ru II (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Ruthenium(II) Complexes of Pyrazolylbenzimidazole Ligands That Inhibit VEGFR2 Phosphorylation

Chakraborty¹,

Roy²,

Chakraborty³

et al. 2021

Inorg. Chem.

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Eight new ruthenium(II) complexes of N,N-chelating pyrazolylbenzimidazole ligands of the general formula [Ru II (p-cym)(L)-X] + [where the ligand L is 2-(1H-pyrazol-1-yl)-1H-benzo [d]imidazole (L1) substituted at the 4 position of the pyrazole ring by Cl (L2), Br (L3), or I (L4) and X = Cl − and I − ] were synthesized and characterized using various analytical techniques. Complexes 1 and 3 were also characterized by single-crystal X-ray crystallography, and they crystallized as a monoclinic crystal system in space groups P2 1 /n and P2 1 /c, respectively. The complexes display good solution stability at physiological pH 7.4. The iodido-coordinated pyrazolylbenzimidazole ruthenium(II) p-cymene complexes (2, 4, 6, and 8) are more resistant toward hydrolysis and have less tendency to form monoaquated complexes in comparison to their chlorido analogues (1, 3, 5, and 7). The halido-substituted 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole ligands, designed as organic-directing molecules, inhibit vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation. In addition, the ruthenium(II) complexes display a potential to bind to DNA bases. The cytotoxicity profile of the complexes (IC 50 ca. 9−12 μM for 4−8) against the triple-negative breast cancer cells (MDA-MB-231) show that most of the complexes are efficient. The lipophilicity and cellular accumulation data of the complexes show a good correlation with the cytotoxicity profile of 1−8. The representative complexes 3 and 7 demonstrate the capability of arresting the cell cycle in the G2/M phase and induce apoptosis. The inhibition of VEGFR2 phosphorylation with the representative ligands L2 and L4 and the corresponding metal complexes 3 and 7 in vitro shows that the organic-directing ligands and their complexes inhibit VEGFR2 phosphorylation. Besides, L2, L4, 3, and 7 inhibit the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and proto-oncogene tyrosine-protein kinase (Src), capable of acting downstream of VEGFR2 as well as independently. Compounds L2, L4, 3, and 7 have a lesser effect on ERK1/2 and more prominently affect Src phosphorylation. We extended the study for L2 and 3 in the Tg(fli1:gfp) zebrafish model and found that L2 is more effective in vivo compared to 3 in inhibiting angiogenesis.

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“…[3,[10][11][12][13][14] The unique properties of transition metal complexes such as varied coordination number, geometries, structural diversity, and easy functionalization of ligands, versatile redox states and distinct photophysical properties offer new opportunities to design an incredible variety of complexes which makes them promising candidates for the application in medicine and in other areas of biological sciences. [3,[10][11][12][13][14][15][16][17][18][19][20] In the recent years, the development of metallotherapeutics as antimalarial agents has gained significant interest in medicinal inorganic chemistry. [3,[21][22][23] In particular, the landmark discovery of ferroquine, [24][25][26] a ferrocene-chloroquine (CQ) conjugate currently undergoing phase IIb clinical trials, has encouraged the design of novel metal complexes for the treatment of parasitic diseases.…”

Section: Introductionmentioning

confidence: 99%

Development of Mitochondria Targeting AIE‐Active Cyclometalated Iridium Complexes as Potent Antimalarial Agents

Kumari

Gupta

Sah

et al. 2022

Adv Healthcare Materials

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The emergence of resistance to conventional antimalarial treatments remains a major cause for concern. New drugs that target the distinct development stages of Plasmodium parasites are required to address this risk. Herein, water‐soluble aggregation‐induced emission active cyclometalated iridium(III) polypyridyl complexes (Ir1–Ir12) are developed for the elimination of malaria parasites. Remarkably, these complexes show potent antimalarial activity in low nanomolar range against 3D7 (chloroquine and artemisinin sensitive strain), RKL9 (chloroquine resistant strain), and R539T (artemisinin resistant strains) strains of Plasmodium falciparum with faster killing rate of malaria parasites. Concomitantly, these complexes exhibit efficient in vivo antimalarial activity against both the asexual and gametocyte stages of Plasmodium berghei malaria parasite, suggesting promising transmission‐blocking potential. The complexes tend to localize into mitochondria of P. falciparum determined by image and cell‐based assay. The mechanistic studies reveal that these complexes exert their antimalarial activity by increasing reactive oxygen species levels and disrupting its mitochondrial membrane potential. Furthermore, the mitochondrial‐dependent antimalarial activity of these complexes is confirmed in yeast model. Thus, this study for the first time highlights the potential role of targeting P. falciparum mitochondria by iridium complexes in discovering and developing the next‐generation antimalarial agents for treating multidrug resistant malaria parasites.

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Metal‐Containing Pharmacophores in Molecularly Targeted Anticancer Therapies and Diagnostics

Cited by 19 publications

References 87 publications

Synthesis and Antiparasitic Activity of New Conjugates—Organic Drugs Tethered to Trithiolato-Bridged Dinuclear Ruthenium(II)–Arene Complexes

Synthesis and Antiparasitic Activity of New Conjugates—Organic Drugs Tethered to Trithiolato-Bridged Dinuclear Ruthenium(II)–Arene Complexes

Cytotoxic Ruthenium(II) Complexes of Pyrazolylbenzimidazole Ligands That Inhibit VEGFR2 Phosphorylation

Development of Mitochondria Targeting AIE‐Active Cyclometalated Iridium Complexes as Potent Antimalarial Agents

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