Author: Justin Jeff WilsonPublisher:
ISBN:
Category :
Languages : en
Pages : 345
Book Description
(cont'd) Chapter 6. Synthesis, Characterization, and Cytotoxicity of Platinum(IV) Dicarbamate Complexes The reaction of cis,cis,trans-[Pt(NH3)2Cl2(OH)2] with alkyl and aryl isocyanates (RNCO) in DMF afforded dicarbamate complexes of the general formula cis,cis,trans- [Pt(NH 3)2Cl 2(O 2CNHR)2]. The resulting complexes were fully characterized by X-ray crystallography, multinuclear NMR spectroscopy, and cyclic voltammetry. The anticancer activities of these complexes were assessed in human lung cancer (A549) and human lung fibroblast (MRC-5) cell lines. Although no clear structure-activity relationships could be delineated, the complexes exhibited activity on the same order of magnitude as that of the clinically established drug cisplatin. Therefore, the reaction of cis,cis,trans-[Pt(NH3)2Cl 2(OH)2] with isocyanates provides a powerful new synthetic pathway to functionalize platinum(IV) anticancer agents. Appendix A. Aqueous Electrochemistry of a Platinum(IV) Prodrug Electrochemical studies of cis,cis,trans-[Pt(NH3)2Cl2(OAc) 2] in aqueous media were carried out. Cyclic voltammetry in pH 7.4 phosphate-buffered saline with glassy carbon and Pt disk working electrodes gave substantially different peak potentials for the irreversible reduction feature. Under these conditions, the glassy carbon electrode was plated with platinum metal derived from the platinum(IV) complex, as determined by cyclic voltammetry and chronoamperometry experiments. The bulk electrolysis of cis,cis,trans-[Pt(NH3)2Cl2(OAc)2] in aqueous solution at a carbon felt working electrode was investigated by 1H NMR spectroscopy. These studies indicate ligand loss upon reduction from both axial and equatorial sites of the platinum(IV) complex. Appendix B. Targeting the Mitochondria with Platinum Anticancer Agents using Mitochondria-Penetrating Peptides Early results of a collaborative effort with the lab of Professor Shana 0. Kelley at the University of Toronto to deliver platinum anticancer agents to the mitochondria are presented. Succinylacetone (Hsuccac) was used as a leaving group ligand for a cis-diammineplatinum(II) complex. The complex [Pt(succac)(NH 3)2](NO3), which contains a terminal, uncoordinated carboxylic acid functional group, was prepared and fully characterized. This complex was conjugated to a mitochondria-penetrating peptide (MPP) using standard solid-phase coupling chemistry. The anticancer activity of the Pt-MPP construct was tested in both wild-type and cisplatin-resistant ovarian cancer cell lines, A2780 and A2780CP70. Although less potent than cisplatin, the construct is equally toxic to both cell lines, thereby indicating that targeting the mitochondria provides a viable strategy for circumventing resistance to platinum drugs. Appendix C. Synthesis and Characterization of Several Novel Platinum Complexes Throughout the course of this thesis work, several platinum complexes were synthesized and characterized, but ultimately not fully pursued as potential anticancer agents. These species include platinum compounds with dichloroacetate, 2,2'-bis(1- methylimidazolyl)phenylmethoxymethane (BIPhMe), nitrogen mustard-containing, and nitroimidazole-derivatized ligands. The syntheses and characterization of these compounds are reported. Crystal structures are described for several of them.