Synthetic strategies for the design of platinum anticancer drug candidates

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.

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2013

Author dc:creator

• Wilson, Justin Jeff

Advisor dc:contributor.advisor

• Stephen J. Lippard.

• Chemistry.

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• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/82326

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/82326