Development of new bioorganometallic metallodendrimers as in vitro anticancer agents

Includes bibliographical references.The clinical success of cisplatin and its derivatives for the treatment of different cancers has had a profound effect on the use of metal-containing agents in medicine. Despite the successes, the drawbacks of platinum-based therapy, such as drug resistance, toxicity and the emergence of unwanted side effects, have bred a need for effective and novel anticancer agents. Hence, the design and study of bioorganometallic complexes as potential therapeutic agents may eventually lead to the identification of new drug candidates. The purpose of this study was to synthesize and characterize a series of polynuclear transition-metal-containing complexes based on a (poly)propyleneimine dendritic scaffold, and investigate the in vitro antiproliferative activity of these complexes

Synthesis, characterization and anticancer studies of multinuclear ruthenium(II) arene complexes based on a dendritic scaffold

Includes bibliographical references.A series of monodentate (N-) and chelating bidentate (N,N-, N,O-), monomeric and dendritic ligands based on a poly(propyleneimine) dendrimer scaffold were synthesized via Schiff base condensation reactions of the relevant amine and appropriate aldehydes. These reactions yielded air- and moisture-stable oils or solids. These ligands contained pyridyl-imine moieties and salicylaldimine moieties. These compounds were isolated in good yields and characterized using standard spectroscopic and spectrometric, analytical techniques

Regulating the anticancer properties of organometallic dendrimers using pyridylferrocene entities: synthesis, cytotoxicity and DNA binding studies

A new series of eight first- and second-generation heterometallic ferrocenyl-derived metal-arene metallodendrimers, containing ruthenium(II) p-cymene, ruthenium(II)-hexamethylbenzene, rhodium(III)-cyclopentadienyl or iridium(III)-cyclopentadienyl moieties have been prepared. The metallodendrimers were synthesized by first reacting DAB-(NH2)(n), (where n = 4 or 8, DAB = diaminobutane) with salicylaldehyde, and then the Schiff-base dendritic ligands were reacted in a one-pot reaction with the appropriate [(eta(6)-p-iPrC(6)H(4)Me)RuCl2](2), [(eta(6)-C6Me6)RuCl2](2), [(eta(5)-C5Me5)IrCl2](2) or [(eta(5)-C5Me5)RhCl2](2) dimers, in the presence of 4-pyridylferrocene. Heterometallic binuclear analogues were prepared as models of the larger metallodendrimers. All complexes have been characterized using analytical and spectroscopic methods. The cytotoxicity of the heterometallic metallodendrimers and their binuclear analogues were evaluated against A2780 cisplatin-sensitive and A2780cisR cisplatin-resistant human ovarian cancer cell lines and against a non-tumorigenic HEK-293 human embryonic kidney cell tine. The second generation Ru(II)-eta(6)-C6Me6 metallodendrimer is the most cytotoxic and selective compound. DNA binding experiments reveal that a possible mode-of-action of these compounds involves non-covalent interactions with DNA

Higher generation cationic N,N-ruthenium(II)-ethylene-glycol-derived metallodendrimers: Synthesis, characterization and cytotoxicity

A new series of higher generation cationic N,N-chelating, ruthenium(II)-ethylene-glycol metallodendrimers from first-, second-, third- and fourth-generation pyridylimine-based poly(propylene) dendrimer scaffolds of the type, DAB-(NH2) (where n = 4, 8, 16 or 32, DAB = diaminobutane) have been prepared. Four metallodendrimers were synthesized, by first reacting DAB-(NH2) with 2pyridinecarboxaldehyde; and subsequently reacting the Schiff-base dendritic ligands with the [(126C(6)H(5)OCH(2)CH(2)OH)RuCl2 dimer, via a bridge-splitting reaction. All compounds were fully characterized using numerous spectroscopic and analytical techniques. In vitro anticancer activities of the complexes were evaluated against the A2780 cisplatin-sensitive and A2780cisR cisplatin-resistant human ovarian carcinoma cell lines and against the non-tumorigenic HEK-293 human embryonic kidney cell line, with the largest dendrimer being the most cytotoxic and selective of all the compounds. A mononuclear model analog was prepared to investigate the size dependency of the systems towards the biological activity. (C) 2015 Elsevier By. All rights reserved

Next Generation PhotoCORMs: Polynuclear Tricarbonylmanganese(I)-Functionalized Polypyridyl Metallodendrimers

The first CO-releasing metallodendrimers, based on polypyridyl dendritic scaffolds functionalized with Mn­(CO)₃ moieties, of the general formula [DAB-PPI-{MnBr­(bpy^CH3,CHN)­(CO)₃}_<i>n</i>], where DAB = 1,4-diaminobutane, PPI = poly­(propyleneimine), bpy = bipyridyl, and <i>n</i> = 4 for first- or <i>n</i> = 8 for second-generation dendrimers, were synthesized and comprehensively characterized by analytical (HR-ESI mass spectrometry and elemental analysis) and spectroscopic (¹H, ¹³C­{¹H}-NMR, infrared, and UV/vis spectroscopy) methods. The CO-release properties of these compounds were investigated in pure buffer and using the myoglobin assay. Both metallodendrimer generations are stable in the dark in aqueous buffer for up to 16 h but show photoactivated CO release upon excitation at 410 nm, representing a novel class of macromolecular photoactivatable CO-releasing molecules (PhotoCORMs). No scaling effects were observed since both metallodendrimers release ∼65% of the total number of CO ligands per molecule, regardless of the generation number. In addition, the mononuclear model complex [MnBr­(bpy^{CH3,CHNCH2CH2CH3})­(CO)₃] was prepared and comprehensively studied, including DFT/TDDFT calculations. These metallodendrimer-based PhotoCORMs afford new methods of targeted delivery of large amounts of carbon monoxide to cellular systems

Anticancer activity of multinuclear arene ruthenium complexes coordinated to dendritic polypyridyl scaffolds

The rational development of multinuclear arene ruthenium complexes (arene = p-cymene, hexamethylbenzene) from generation 1 (G1) and generation 2 (G2) of 4-iminopyridyl based poly(propyleneimine) dendrimer scaffolds of the type, DAB-(NH2)n (n = 4 or 8, DAB = diaminobutane) has been accomplished in order to exploit the ‘enhanced permeability and retention’ (EPR) effect that allows large molecules to selectively enter cancer cells. Four compounds were synthesised, i.e. [{(p-cymene)RuCl2}4G1] (1), [{(hexamethylbenzene)RuCl2}4G1] (2), [{(p-cymene)RuCl2}8G2] (3), and [{(hexamethylbenzene)RuCl2}8G2] (4), by first reacting DAB-(NH2)n with 4-pyridinecarboxaldehyde and subsequently metallating the iminopyridyl dendrimers with [(p-cymene)RuCl2]sub>2 or [(hexamethylbenzene)RuCl2]2. The related mononuclear complexes [(p-cymene)RuCl2(L)] (5) and [(hexamethylbenzene)RuCl2 (L)] (6) were obtained in a similar manner from N-(pyridin-4-ylmethylene)propan-1-amine (L). The molecular structure of 5 has been determined by X-ray diffraction analysis and the in vitro anticancer activities of the mono-, tetra- and octanuclear complexes 1–6 studied on the A2780 human ovarian carcinoma cell line showing a close correlation between the size of the compound and cytotoxicity

Synthesis of CpM(CO)(3)-DAB and -PAMAM Dendrimer Conjugates and Preliminary Evaluation of Their Biological Activity

Dendrimers of different generations and core structures [diaminobutane poly(propylenimine) (DAB) G1, G2, G3; poly( amidoamine) (PAMAM) G1] were chosen as carriers for bioactive organometallic half-sandwich complexes of the type CpM(CO)(3) (Cp = cyclopentadienyl, M = Mn or Re) to study the influence of these parameters on their biological activity against cancer cells. Structure-activity relationships were determined by variation of the metal center as well as the type, molecular weight, and number of terminal functional groups of the dendrimer conjugates. All conjugates were characterized by IR and NMR spectroscopy as well as HPLC. Their biological activity was determined on MCF-7 human breast cancer cells by the resazurin assay. Interestingly, the mostactive compounds were the first-generation dendrimer conjugates. The Mn and Re series showed nearly the same activities. Thus, the cytotoxicity of the dendrimer conjugates does not seem to directly correlate with the type or number of terminal functional groups. Rather, it points to a mechanism of action that is different from that previously observed for peptide conjugates with similar CpM(CO)(3) functional groups

Evaluation of the in vitro anticancer activity of cyclometalated half-sandwich rhodium and iridium complexes coordinated to naphthaldimine-based poly(propyleneimine) dendritic scaffolds

The development of cyclometalated rhodium and iridium complexes from first-and second-generation naphthaldimine-based poly(propyleneimine) dendrimer scaffolds of the type, DAB-(NH2)(n) (where n = 4 or 8, DAB = diaminobutane) has been accomplished. Four metallodendrimers were synthesised, viz. (Cp*MCl)(4)G(n) (1-4), by first reacting DAB-(NH2)(n) with napththaldehyde and subsequently metallating the Schiff-base dendrimers with the dimers [Cp*MCl2](2) (where M = Rh or Ir). Related mononuclear complexes [Cp*MCl(L)] (L = naphthaldimine) (5-6) were obtained in a similar manner. The molecular structures of 5 and 6 have been determined by single-crystal X-ray diffraction analysis and the in vitro anticancer activities of 1-6 were evaluated against the A2780 and A2780cisR human ovarian carcinoma cell lines. (C) 2014 Elsevier B.V. All rights reserved

Antimalarial activity of ruthenium(ii) and osmium(ii) arene complexes with mono- and bidentate chloroquine analogue ligands

Eight new ruthenium and five new osmium p-cymene half-sandwich complexes have been synthesized, characterized and evaluated for antimalarial activity. All complexes contain ligands that are based on a 4-chloroquinoline framework related to the antimalarial drug chloroquine. Ligands HL1–8 are salicylaldimine derivatives, where HL1 = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine, and HL2–8 contain non-hydrogen substituents in the 3-position of the salicylaldimine ring, viz. F, Cl, Br, I, NO2, OMe and tBu for HL2–8, respectively. Ligand HL9 is also a salicylaldimine-containing ligand with substitutions in both 3- and 5-positions of the salicylaldimine moiety, i.e. N-(2-((2-hydroxy-3,5-di-tert-butylphenyl)methyl-imino)ethyl)-7-chloroquinolin-4-amine, while HL10 is N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) The half sandwich metal complexes that have been investigated are [Ru(η6-cym)(L1–8)Cl] (Ru-1–Ru-8, cym = p-cymene), [Os(η6-cym)(L1–3,5,7)Cl] (Os-1–Os-3, Os-5, and Os-7), [M(η6-cym)(HL9)Cl2] (M = Ru, Ru-HL9; M = Os, Os-HL9) and [M(η6-cym)(L10)Cl]Cl (M = Ru, Ru-10; M = Os, Os-10). In complexes Ru-1–Ru-8 and Ru-10, Os-1–Os-3, Os-5 and Os-7 and Os-10, the ligands were found to coordinate as bidentate N,O- and N,N-chelates, while in complexes Ru-HL9 and Os-HL9, monodentate coordination of the ligands through the quinoline nitrogen was established. The antimalarial activity of the new ligands and complexes was evaluated against chloroquine sensitive (NF54 and D10) and chloroquine resistant (Dd2) Plasmodium falciparum malaria parasite strains. Coordination of ruthenium and osmium arene moieties to the ligands resulted in lower antiplasmodial activities relative to the free ligands, but the resistance index is better for the ruthenium complexes compared to chloroquine. Overall, osmium complexes appeared to be less active than the corresponding ruthenium complexes