Macromolecular metal compounds in cancer research: Concepts and synthetic approaches

Abstract

m:The anticancer activity of metal compounds has been a topic of major interest in drug research for two decades. Platinum compounds, in particular, including cisplatin w-diamminedichloroplatinum(1l)) and second generation derivatives, have for many years been among the leading drugs administered in clinical cancer therapy, although excessive toxicity, induction of drug resistance, and other formidable, debimental side effects continue to militate against efficacious utilization and achievement of satisfactory cure rates. Adding to the toxicity problem, most bioactive metal complexes dissolve poorly, if at all, in aqueous media, possess low stability in solution, undergo rapid depletion from central circulation, and often times are prevented from smooth cell entry by molecular charge or polarity. The concept of polymer-drug conjugation, designed to overcome the pharmacokinetic barriers to satisfactory clinical chemotherapy with present-day anticancer drugs, is finding increasing acceptance in biomedical research. The concept has been utilized in our laboratory for the purpose of enhancing the effectiveness of metal-containing carcinostatic agents. In the present communication we demonstrate the practicability of synthesizing platinum-, iron-, and tin-containing polymer conjugates that are biodegradable, dissolve completely in water, and are structurally designed so as to permit release of the active metal compound in the biological environment. Following a brief review of initial results, we discuss selected synthetic approaches and obtained conjugates, in which the metals are bound to polymer-attached ligands as dichloroplatinum(II), di-tfcyclopentadienyliron, and diorganotin(1V) moieties.

Synthesis, characterization and thermal degradation kinetics of ferrocene-containing aramids

“…Ferrocene monomer (1,1 -ferrocenedicarboxylic acid chloride) was prepared using reported methods 24,25 starting from ferrocene using thionyl chloride as chlorinating agent in dichloromethane with triethylamine as catalyst (Fig. 1).…”

“…in cancer treatment. 24 Our interest was to study the effect of incorporation of ferrocene as an aromatic diacid chloride into aramid backbones using low-temperature solution polycondensation techniques. One such example reported in literature involves the interfacial condensation of 1,1 -ferrocenedicarboxylic acid chloride with p-phenylene diamine.…”

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

“…A plethora of publications, including major contributions from the author's laboratory, attest to the feasibility and resultant pharmaceutical improvements of this approach [34][35][36][37][38][39][40][41][42][43]. Earlier reviews are available [17,20,44,45], and the recent report in a book chapter by Siegmann and Carraher [19] provides a summarizing and quite illuminating survey. As more recently the benefits of the carboplatin skeletal arrangement around the Pt atom became increasingly evident, the goals of polymer conjugation research shifted to a different drug binding strategy, whereby the metal is coordinated by two carrier-attached carboxylato ligands, thus permitting drug release via hydrolytically cleaved -COO − leaving groups.…”

Synthesis and Preliminary Bio-evaluation of Polyaspartamide Co-conjugates of p-Amino-salicylic Acid Chelated Platinum(II) and Ferrocene Complexes

“…The neutral ferrocene complex readily undergoes one-electron oxidation, transforming to the ferricenium cation. Many biological interactions involve free radical chemistry, frequently with the participation of reactive oxygen species, and the ferrocene/ferricenium couple, and when placed into such biological environment, can be expected to play an active part in it [21,23,24].…”