Polymeric Conjugates of Selected Aminoquinoline Derivatives as Potential Drug Adjuvants in Cancer Chemotherapy Blessing A. Aderibigbe • Kayembe D. Jacques • Eberhard W. Neuse Received: 23 December 2010 / Accepted: 24 January 2011 / Published online: 9 February 2011 Ó Springer Science+Business Media, LLC 2011 Abstract In the chemotherapy of cancerous diseases, the clinical co-administration of an active anti-tumor drug with other compounds acting as potentiating agents or adjuvants has demonstrated considerable merits in comparison with single-drug administration. Selected members of the 4- and 8-aminoquinoline-based class of antimalarials, such as chloroquine and hydroxychloroquine, have been identified as providers of such adjuvant effects in combination with certain standard antitumor drugs, although no significant clinical experiences have as yet been reported. The here described project aims at the synthesis of water-soluble macromolecular carriers to which selected aminoquino- lines are bioreversibly conjugated together with cytotoxic drug species exemplified by a diaminoplatinum(II) com- plex and by the organoiron compound, ferrocene, the latter being a relative newcomer to the family of organometallic antineoplastic agents. As most medicinal agents differ from each other by their pharmacokinetic path and, therefore, experience different rates and degree of body distribution and organ accumulation, the simultaneous availability of two or more mutually potentiating drug species can best be achieved if a common transport vehicle, such as a multi- functional carrier polymer of the type synthesized in this study, is utilized for this purpose. The conjugates and co-conjugates, isolated by conventional methods as water- soluble solids, are compositionally characterized by NMR- spectroscopic and microanalytical techniques. Keywords 8-aminoquinolines Á 4-aminoquinolines Á Ferrocene Á Platination reaction Á 4-aminoquinoline homoconjugates Á 8-aminoquinoline homoconjugates Á Polymeric co-conjugates Á Drug adjuvants 1 Introduction In cancer chemotherapy the co-administration of two dif- ferently acting antineoplastic agents, or else of an active anticancer drug with a non-cytotoxic, yet potentiating agent, has advanced in the last decade to a highly effica- cious treatment modality. Commonly referred to as com- bination therapy, this modality takes advantage of the capability of certain bioactive compounds to potentiate each other when co-administered, creating synergy. In more recent years the 4-aminoquinoline derivative, chloroquine, N 4 -(7-chloroquinolin-4-yl)-N 1 ,N 1 -dimethyl- 1,4-pentanediamine, which ahs made a name for itself in the chemotherapy of malaria (for a classical review, see [1]), has moved into the limelight of combination drug research as a potential co-drug. While we are not aware of clinical trials or even comprehensive in vivo screens, the compound has been found to reduce multi-drug resistance and enhance the cytotoxic activity of selected antineo- plastic drug systems [2, 3]. Chloroquine also enhances radiation lethality (in HeLa cells) by combined radio- potentiation, where it interferes with the repair of radiation- damaged DNA [4]. Similar findings implicate the quinoline derivatives hydroxychloroquine and primaquine as active combination drugs. Of particular interest is the observation of improved mid-term survival of patients afflicted with the infiltrative and strongly resistant glioblastoma multiforme in adjuvant therapies of chloroquine combined with conventional therapeutic modalities [3]. The mechanism of B. A. Aderibigbe (&) Á K. D. Jacques Á E. W. Neuse (&) School of Chemistry, University of the Witwatersrand, Private Bag 3, Wits 2050, South Africa e-mail: blessingaderibigbe@gmail.com E. W. Neuse e-mail: eberhard.neuse@wits.ac.za 123 J Inorg Organomet Polym (2011) 21:336–345 DOI 10.1007/s10904-011-9461-2