Eberhard W. Neuse

Ferricenium complexes: a new type of water-soluble antitumor agent.

SummaryThe antitumor activity of a series of iron complexes, i.e., of ferrocene [Cp2Fe], of tetrachloroferrates(III) [R4N]+[FeCl4]-, and of ferricenium complexes [Cp2Fe]+X- (X-=[FeCl4]-, 1/2[Cl3FeOFeCl3]2-, [H5Mo7O24]-·2H2O, [2,4,6-(NO2)3C6H2O]-, or [CCl3COO]-·2 CCl3COOH) was investigated against EAT in CF1 mice. Whereas ferrocene and the ammonium tetrachloroferrates(III) did not show recognizable tumor-inhibiting activity, such activity was exhibited by the water-soluble, salt-like ferricenium complexes; the best antineoplastic properties, with optimum cure rates of 100%, were found for ferricenium picrate and ferricenium trichloroacetate.The ferricenium compounds are the first iron complexes for which antineoplastic activity has now been shown. They represent a new type of antitumor agent insofar as they differ fundamentally from known inorganic and organometallic antitumor agents (a) by their ionic, salt-like character, which is responsible for their high water solubility, and (b) by the absence of a cis-dihalometal moiety; this moiety has been recognized as important for the intracellular action of other known inorganic cytostatics.

Synthetic Polymers as Drug-Delivery Vehicles in Medicine

Cancerous diseases present a formidable health problem worldwide. While the chemotherapy of cancer, in conjunction with other treatment modalities, has reached a significant level of maturity, efficacious use of such agents is still restricted by numerous pharmacological deficiencies, such as poor water solubility, short serum circulation lifetimes, and low bioavailability resulting from lack of affinity to cancer tissue and inadequate mechanisms of cell entry. More critically still, most drugs suffer from toxic side effects and a risk of drug resistance. The class of platinum anticancer drugs, although outstandingly potent, is particularly notorious in that respect. Among the countless methods developed in recent years in an effort to overcome these deficiencies, the technology of polymer-drug conjugation stands out as a particularly advanced treatment modality. The strategy involves the bioreversible binding, conjugating, of a medicinal agent to a water-soluble macromolecular carrier. Following pharmacokinetic pathways distinctly different from those of the common, nonpolymeric drugs, the conjugate so obtained will act as a prodrug providing safe transport of the bioactive agent to and into the affected, that is, cancerous cell for its ultimate cell-killing activity. The present treatise will acquaint us with the pharmacological fundamentals of this drug delivery approach, applied here specifically to the metalorganic platinum-type drug systems and the organometallic ferrocene drug model. We will see just how this technology leads to conjugates distinctly superior in antiproliferative activity to cisplatin, a clinically used antitumor agent used here as a standard. Polymer-drug conjugation involving metal-based and other medicinal agents has unquestionably matured to a practical tool to the pharmaceutical scientist, and all indications point to an illustrious career for this nascent drug delivery approach in the fight against cancer and other human maladies.

Correlations of substituent parameters with the carbonyl stretching force constant in arenetricarbonylchromium complexes

Abstract Correlations are established between selected substituent parameters (σI,σP, σRP,σPO,σRO) and the carbonyl stretching force constant, k(CO), for 28 mono and poly-substituted tricarbonylchromium-complexed arene compounds. On the basis of the statistical results it is concluded that the overall electronic substituent effect transmitted to the carbonyl groups involves both mesomeric and inductive mechanisms. Within the restricted domain, including substituent group and benzene ring, transmission proceeds largely by resonance, with a minor inductive (through-bond and field) effect operative in the same domain. Further transmission from the substituted arene ring to the chromium atom predominantly involves an inductive mechanism. This result, in support of existing literature data, suggests appreciable participation of the ring carbon σ framework in the metal—ring bond formation.

Electrochemical characterization of some ferrocenylcarboxylic acids

SummarySeveral carboxy-substituted ferrocene compounds are prepared and investigated by cyclic voltammetry in acetonitrile solution. The half-wave potentials of most of the acids studied (E1/2=0.34−0.58 V versus s.c.e.) are more positive than that of ferrocene (0.33 V), reflecting a diminished susceptibility to oxidation of these compounds relative to the parent metallocene. Only β-ferrocenylpropionic acid (0.325 V) is effectively identical with the latter in its oxidation behaviour, and γ-ferrocenylbutyric acid (0.31 V) tends to be more readily oxidized. The results are of interest for subsequent chemical oxidation studies of ferrocenylcarboxylic acids.

Antineoplastic activity of polyaspartamide–ferrocene conjugates †

The ferrocene/ferricenium redox system plays a significant role in biological oxidation, reduction and free-radical reactions. Of particular interest are the findings of earlier investigations which showed certain water-soluble ferricenium salts to possess appreciable antiproliferative activity against various murine tumor lines and a xenografted human colorectal adenocarcinoma. Solubility in water, a prerequisite for efficacious transport and dissipation in central circulation, was then proposed as a principal requirement for the ferrocene complex system to exert antineoplastic activity irrespective of the oxidation state in which it is administered. In order to shed more light on this question, we decided to investigate the antiproliferative properties of polymer–ferrocene conjugates containing the metal complex in the non-oxidized (ferrocene) form while fulfilling the critical requirement of water solubility. To this end, five selected, water-soluble conjugates, synthesized by reversible coupling of 4-ferrocenylbutanoic acid to variously structured polyaspartamides featuring pendant primary amino groups as coupling sites, were tested in vitro against cultured HeLa cells at concentrations up to 50 µg Fe ml−1. Optimal antiproliferative activities, with IC50 in the range of 2–7 µg Fe ml−1, were determined for three compounds possessing tertiary-amine functions susceptible to protonation at physiological pH. Lower activities (IC50 = 45–60 µg Fe ml−1) were demonstrated for two poly(ethylene oxide)-containing conjugates. However, no reasonable structure–performance relationships can be derived at this stage from the small number of compounds tested. Copyright

Polymeric organoiron compounds as prodrugs in cancer research

Ferrocene, di(η 5 -cyclopentadienyl)iron(II)), has for nearly half a century now been a focal point of research activities in the realm of organo-transition-metal chemistry and physics, with ramifications into numerous technologies. More recent years have witnessed the emergence of a new research trend, probing the behavior of ferrocene in the biological realms, notably in the transformed, i.e. cancerous, cell system. Following initial reports attesting to the pronounced antiproliferative properties of certain water-soluble derivatives of ferrocene and its one-electron oxidation product, the ferricenium radical cation, earlier programs were set up in the authors laboratory with the objective of developing water-soluble polymeric conjugates in which the bioactive ferrocene unit is bioreversibly tied to macromolecular carriers in order to enhance its therapeutic effectiveness. In this article, these earlier investigations of polymer-ferrocene conjugation are briefly reviewed, and the current, considerably broadened synthetic program is introduced. The carriers are predominantly of the highly versatile poly(aspartamide) type, but other structures resulting from esteramine polycondensation reactions have been included. Carrier anchoring of the ferrocenylation agent of choice, 4-ferrocenylbutanoic acid, is brought about both by acylation of carrier-attached amino groups, leading to amide links in the spacer, and by acylation of polymer-bound hydroxy groups, resulting in ester linking of the ferrocene unit. Selected conjugates are being screened in cell culture tests for antiproliferative activity against the HeLa and LNCaP human cancer lines, and preliminary results are highly promising, with IC 50 values in the representative range of 2-20 μg Fe/ml. In view of the relatively low level of toxic side effects expected for these organoiron compounds, the findings here presented, however limited in scope, offer challenging opportunities for the development of iron-containing, polymer-anchored drug systems as chemotherapeutic agents in cancer research.

Carrier-bound platinum and iron compounds with carcinostatic properties

The treatment of malignancies with carcinostatic drugs, per se or in combination with other modalities, has proved its value over many decades of clinical administration. However, despite much progress in drug research in recent years, complete cures by chemotherapy are still restricted to a small select number of cancers, whereas, in general, remissions remain incomplete or short lived, notably whenever metastatic lesions have developed or resistance phenomena emerged. In an effort to increase the effectiveness of chemotherapy, several new alleys of development are being pursued world-wide, and one of these, involving the binding of monomeric anticancer drug systems to water-soluble, biocompatible and biodegradable polymeric carriers, is the subject of this paper. Previously developed, polymer-bound cis-diaminedichloroplatinum(II) complexes are briefly discussed. The complex moiety is attached to the polymeric carrier in these conjugates through metal chelation by polymer-connected ethylene–diamine segments. Promising antineoplastic activity is observed in tests against cultured HeLa carcinoma cells, with highest activity (IC50 ≃ 15 μg Pt/ml) shown by a polyarpartamide conjugate comprising the platinum complex as a side group. Monoamine-coordinated platinum(II) complexes carrier-bound through primary amine terminals on short side chains are synthetically accessible by aqueous-phase platination of amine-functionalized carrier polymers. A representative conjugate of this class shows antiproliferative activity (against HeLa cells) well in the general activity range of the cis-diamineplatinum-type polymers, suggesting that, in the polymer-attached state, platinum complex structures deviating from the familiar cis-diamineplatinum chelate pattern may well successfully compete with cisplatin-type drug systems as cytotoxic agents. Organoiron compounds of the ferrocene type represent another drug system discussed in this paper. Ferrocene derivatives have shown highly promising activity both in vitro and in vivo, and carrier-binding of ferrocenes is seen as an efficacious means of increasing their therapeutic effectiveness. A series of water-soluble ferrocene conjugates are presented in which 4-ferrocenylbutanoic acid is reversibly polymer-bound by coupling with pendant amino groups. Activities against HeLa cells are in the same range as those of similar platinum conjugates. In view of low expected toxicities of the organoiron polymers, as compared with the platinum compounds, this finding has significant implications for broad-based development of polymeric ferrocene conjugates.

Water soluble polyamides as potential drug carriers. IX. Polyaspartamides grafted with amine‐terminated poly(ethylene oxide) chains

The synthesis of side-chain-functionalized polyaspartamides as potential carrier polymers for medicinal agents is described. The nucleophilic ring opening in poly-D,L-succinimide, mediated by O,O′-bis(2-aminopropyl)poly(ethylene oxide) (nominal molecular mass is 600) and ethanolamine under carefully controlled experimental conditions leads to the formation of aspartamide polymers bearing hydrosolubilizing hydroxyethyl side groups in addition to variable proportions of poly(ethylene oxide) (PEO) side chains terminated with primary amino groups. The side chain terminals represent functionalities for drug binding, whereas the PEO constituents contribute to overall hydrophilicity and biocompatibility of the carriers and to enhance their biomedical performance by imparting resistance to protein binding and increasing central circulation lifetime. The water-soluble polymeric products are isolated by dialysis (molecular mass cutoff: 25,000) and freeze-drying in typical yields of 40–60%, with inherent viscosities in the range of 10–18 mL g−1. Polymer compositions are determined by 1H NMR spectroscopy and microanalysis. A selected carrier is modified by N-acylation with 4-ferrocenylbutanoic acid as a model drug, giving a ferrocene-containing, water-soluble conjugate, thus demonstrating the accessibility of the terminal amino groups on the PEO side chains to acylating agents and other potential reactants.

Poly(squaryl amides)

Abstract The solution polycondensation of squaric acid with p-phenylenediamine in selected protic, aprotic or strongly acidic solvents furnishes linear polyamide structures possessing units with 1,2- as well as those with 1,3-orientation of the substituent links on the four-membered ring system. The relative occurrence of these two unit types as assessed by infra-red spectroscopy depends on the basicity of the medium, the extent of 1,2-orientation decreasing with increasing solvent basicity. The same type of polyamide results from a solution polycondensation of the diamine with diethyl squarate. These findings, contradicting earlier results of other workers, are in accord with more recent non-polymeric squaric acid amidation studies. A reference polyamide with maximum content of units possessing the 1,2-substituent orientation is synthesized from p-phenylenediamine and squaryl dichloride under low temperature solution polymerization conditions. Polymer inherent viscosities range from about 10 to 30ml/g, highest values being obtained under conditions of homogeneous polymerization.

Synthesis and characterization of water-soluble polyaspartamide-ferrocene conjugates for biomedical applications

Polymer-ferrocene conjugates are synthesized from the polyamide1, poly-α,β-dl-[N-(3-(morpholin-4-yl)propyl)aspartamide-co-N-(2-aminoethyl)aspartamide, through coupling of amino side groups with the carboxyl function in a number of ferrocenylcarboxylic acids, including ferrocenoic acid, ferrocenylacetic acid, 3-ferrocenylpropanoic acid, 3-ferrocenylbutanoic acid, 4-ferrocenylbutanoic acid, and 4-ferrocenyl-4-hydroxypentanoic acid. The ferrocene complex has been chosen for conjugation by virtue of the cytotoxic properties observed with some of its derivatives. The coupling reactions, mediated by HBTU (O-benzotriazolyl-N,N,N′N′-tetramethyluronium hexafluorophosphate), are brought about inN,N-dimethylformamide solution and lead to degrees of substitution in the range of 25–95%. The resulting conjugates2, fractionated by dialysis in tubing with a 12,000–14,000 molecular mass cutoff and collected in the solid state by freeze-drying, are completely soluble in water after isolation and retain this property in frozen aqueous solutions. Preliminary electrochemical data are reported, indicating a decreasing (i.e., less positive) potential with increasing length of the aliphatic, electron-donating connecting link between the ferrocene and the carboxamide anchoring group. The 4-ferrocenylbutanoyl substituent is associated with the least positive potential of those structures investigated and, hence, should provide conjugates with optimalin vivo stability in the ferricenium state. Selected conjugates will be submitted to screening tests for antineoplastic activity.