Author

Pooja Ahuja

Graduation Semester and Year

2016

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Frederick M MacDonnell

Abstract

The ruthenium polypyridyl complexes [(phen)2Ru(tatpp)Ru(phen)2]4+ ([P]4+) and [(phen)2Ru(tatpp)]2+ ([MP]2+) are promising anti-tumor agents that arrest H358 NSCLC tumor growth in mouse tumor models and show cytotoxicity in the low micromolar range towards a number of platinum sensitive NSCLC lines (H358, H226, HOP62, H2087). Dose escalation toxicity studies in mice reveal that [MP]2+ and [P]4+ are tolerated without any short term side effects at levels up to 40 mg drug/kg mouse and >160 mg drug/kg mouse respectively with no obvious side effects, when administered as IP injection. Mechanistic studies reveal that much of the anti-tumor activity is primarily due to the presence of redox active ligand unit tatpp that binds to DNA via intercalation and is then reduced to a radical species that cleaves DNA via H-atom abstraction from the deoxyribose unit. In this work, we examine the hypothesis that the tatpp ligand is the key pharmacophore and that coordination to Ru(II) is needed primarily to enhance its solubility and modify its reduction potential, however other transition metals may also satisfy this requirement. In an effort to determine the generality of the tatpp pharmacophore, a number of Re(I) analogues were targeted and tested, where possible, for DNA cleavage activity, cytotoxicity, and animal toxicity. The Re(I)tatpp analogues possess lower overall charge and differing coordination environments around tatpp which could potentially alter the spectrum of cytotoxic activity against cancer cells and open new potential therapies. In this regards, we prepared a series of homometallic and heterobimetallic Re(I)tatpp analogues such as Re2(CO)6(tatpp)Cl2 [ReP], Re(CO)3(tatpp)Cl [MRe], [Re2(CO)6 (tatpp)(CH3CN)2](PF6)2 [RePCH3CN]2+,[Ru(phen)2(tatpp)Re(CO)3(CH3CN)](PF6)3 [RuReCH3CN]3+, [Ru(phen)2(tatpp)Re(CO)3(P(CH2OH)3](PF6)3 [RuRePR3]3+ and characterized them by 1H NMR, IR, HRMS, CHN. Unlike Ru(II) complexes [P]4+and [MP]2+, Re(I)tatpp complex [RePCH3CN]2+ was found to be air sensitive and oxidizes to form a quinone analogue [Re2(CO)6(tatpq)(CH3CN)2](PF6)2 [ReQ]2+ upon visible light irradiation in solution. The compound also can dimerize, whether in solution or solid state, to form a ‘dimer of dimers’ [Re4(CO)12(tatpp)2(CH3CN)4](PF6)4 [d-RePCH3CN]4+ via an unknown route. The heterobimetallic complex [RuReCH3CN]3+ was found to be less reactive than [RePCH3CN]2+ but will also undergo photooxidation to the quinone analogue [Ru(phen)2(tatpq)Re(CO)3(CH3CN)](PF6)3 [RuReQCH3CN]3+ after prolonged irradiation of over 72 h under identical conditions (relatively low yield - 33%). Because of solubility reasons, only [RuReCH3CN]3+ and [RuRePR3]3+ were screened for DNA cleavage activity which revealed that these complexes are effective DNA cleaving agents under the same conditions in which Ru(II) complexes [P]4+ and [MP]2+ are. Toxicity studies reveal that [RuRePR3]3+ exhibits different spectrum of cytotoxicity against four cancer cell lines and low animal toxicity (MTD > 160 mg/kg mouse). Biodistribution study reveal gradual body clearance while the mass spectrometry data to support renal clearance is awaited. Representative HPLC studies to show that [RuRePR3]3+ is not only pure but unexpectedly fluorescent are also presented. Confocal microscopy study in H358 cells to determine patterns of uptake and localization is also presented and discussed.

Keywords

Photooxidation, DNA cleavage, Fluorescence, HPLC, Cytotoxicity, Animal toxicity, Anticancer

Disciplines

Chemistry | Physical Sciences and Mathematics

Comments

Degree granted by The University of Texas at Arlington

Included in

Chemistry Commons

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