Synthetic strategies for the design of platinum anticancer drug candidates
Author(s)Wilson, Justin Jeff
Massachusetts Institute of Technology. Department of Chemistry.
Stephen J. Lippard.
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Chapter 1. The Synthetic Chemistry of Platinum Anticancer Agents Since the inception of cisplatin as a clinically approved anticancer agent, a large number of platinum compounds have been synthesized with the aim of finding new, improved drugs. As a result of these efforts, only two additional platinum-based drugs received FDA approval for the treatment of cancer. Nevertheless, fundamental advancements in the synthetic chemistry of platinum arose from these research endeavors. This chapter presents a comprehensive review of synthetic methods for the preparation of classic and non-conventional platinum compounds with therapeutic potential. Chapter 2. Platinum(II) Complexes Bearing Fluorescent Di-2-Pyridylmethane Ligands A strategy to investigate the cellular uptake and localization of platinum anticancer agents is to label them with a fluorescent ligand. In pursuit of this strategy, three new platinum(II) complexes with modified di-2-pyridylmethane (dpm) ligands, two of which are fluorescent, were prepared. These new ligands contain either a non-fluorescent tosyl group (Ts-dpm) or fluorescent NBD or dansyl group (NBD-dpm and dansyl-dpm). The photophysical and solution conformational properties of the complexes [Pt(dpm')C12], where dpm' is one of the three ligands described above, are presented. The thermal and photolytic decomposition products and the hydrogen peroxide oxidation products were investigated. Chapter 3. Outer-Sphere Amide Bond Coupling Reactions for the Preparation of a Fluorescent Platinum(IV) Redox Sensor Because of the poor solubility, stability, and lack of structural similarity to clinically used platinum anticancer agents of the complexes described in Chapter 2, synthetic strategies were devised to prepare alternative fluorescent platinum compounds. The dangling carboxylic acid groups of the platinum(II) complexes [Pt(edma)C 2] and [Pt(edda)C12], where edma = ethylenediamine-N-acetic acid and edda = ethylenediamine-N,N'-diacetic acid, were functionalized by amide bond coupling using benzyl amine. For [Pt(edda)C12], the resulting product was a mixture of diastereomers owing to chirality at both coordinating nitrogen atoms. Only [Pt(edma)C12] was further modified by coupling it to dansyl ethylenediamine to form [Pt(edDS)C12], where edDs is the dansyl ethylenediamine-containing ligand. Upon oxidation of this complex with iodobenzene dichloride, the emission of the dansyl fluorophore was substantially quenched. By reducing the oxidized product [Pt(edDs)C14] with an excess of the biological reducing agents glutathione, cysteine, and ascorbic acid in aqueous buffer, a 6.3-fold turn-on in emission intensity was observed. This turn-on response suggests that [Pt(edDs)C14] and its anologues may serve as fluorescent redox sensors to monitor the reduction of platinum(IV) in living cells. Chapter 4. In Vitro Anticancer Activity of Platinum(II) Complexes with p-Diketonate Leaving Group Ligands To investigate the role of the leaving group ligand on the anticancer activity of platinum(II) complexes, five compounds with the general formula [Pt(NH3)2([beta]-diketonate)]+ were prepared and characterized. The [beta]-diketonate ligands were chosen to tune the lipophilicity and electrophilicity of the resulting complexes. Three general synthetic protocols for preparing such complexes were established. These compounds were tested for anticancer activity in a panel of four different cell lines. Structure-activity relationships were derived, correlating high cytotoxicity with increasing lipophilicity and decreasing donor strength of the p-diketonate. Chapter 5. Acetate-Bridged Dinuclear Platinum(III) Complexes Derived from Cisplatin The oxidation chemistry of a previously reported acetate-bridged dinuclear cisdiammineplatinum( II) complex, cis-[Pt"(NH 3)2(p-OAc) 2Pt"(NH 3)2](NO 3)2, was explored. Treatment of this complex with either PhICl2 or Br2 afforded the 2-electron oxidized halidecapped dinuclear complexes, cis-[XPt"I(NH 3)2([beta]-OAc) 2Ptl"(NH3)2X](NO3)2, where X is either bromine or chlorine. The platinum(II) and platinum(III) complexes were fully characterized by X-ray crystallography and multinuclear NMR spectroscopy. The oxidation of cis-[Ptr(NH3)2([mu]t-OAc)2PtIII(NH3)([mu]-NH2)]2(NO3)2 with PhI(O2CCF3)2 and XeF2 was also explored. The use of PhI(O2CCF3)2 gave the unexpected amido-bridged tetranuclear platinum(III) complex, cis-[(O2CCF3)PtIII(NH3)2([mu](pi-OAc)2PtIII(NH3)([mu]-NH2)]2(NO3)4, which was characterized structurally by X-ray crystallography. From the analogous reaction using XeF2 instead of PhI(O 2CCF3 )2 , yellow crystals were obtained, and the crystal structure revealed an infinite chain of acetatebridged dinuclear platinum units.(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.
Thesis (Ph. D. in Inorganic Chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013.Cataloged from PDF version of thesis. Vita.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Chemistry.
Massachusetts Institute of Technology