Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor's Name

Stanislaw F. Wnuk

First Advisor's Committee Title

Major Professor

Second Advisor's Name

David Chatfield

Second Advisor's Committee Title

committee member

Third Advisor's Name

Watson Lees

Third Advisor's Committee Title

committee member

Fourth Advisor's Name

Kevin O'Shea

Fourth Advisor's Committee Title

committee member

Fifth Advisor's Name

John Makemson

Fifth Advisor's Committee Title

committee member

Keywords

gemcitabine, silicon-fluoride PET, 18F PET

Date of Defense

6-26-2017

Abstract

Gemcitabine (dFdC) is an effective chemotherapeutic nucleoside analogue for treatment of cancers and solid tumors. Gemcitabine’s chemotherapeutic effect is limited by its rapid intracellular deamination by cytidine deaminase into the inactive uracil derivative. Herein, I designed and synthesized two sets of gemcitabine analogues: i) a 4-N-alkyl gemcitabine analogue containing a β-keto sulfonate moiety, and ii) clickable analogues possessing silicon-fluoride acceptor building blocks. Both of these sets of analogues undergo efficient fluorination, including fluorination protocols compatible with 18F labeling.

The synthesis of the 4-N-alkyl gemcitabine analogue bearing β-keto sulfonate moiety began with reaction of 4-N-tosylgemcitabine with 1-amino-10-undecene, followed by a series of oxidation and sulfonation steps which yielded the β-keto sulfonate analogues.

The coupling of gemcitabine with carboxylic acids using peptide coupling conditions afforded 4-N-alkanoyl analogues with a terminal alkyne or azido moiety. Click reaction of these 4-N-alkanoyl analogues with dialkylsilyl building blocks gave 4-N-alkanoylsilanegemcitabine analogue. Reaction of 4-N-tosylgemcitabine with vii functionalized azidoalkyl amines provided 4-N-alkylgemcitabine with a terminal azido group. Coupling of the latter with dialkylsilyl building block provided 4-N-alkylsilanegemcitabine. Fluorination of 4-N-alkyl gemcitabine analogues with β-keto sulfonate moieties and of the trisubstituted silane derivatives with KF and 18-Crown-6 (CH3CN/75°C/0.5-1h), gave the corresponding fluorinated 4-N-alkyl and alkanoyl gemcitabine analogues under conditions that are compatible with protocols for positron emission tomography (PET) 18F labeling. The [18F] 4-N-alkyl and alkanoyl silane gemcitabine analogues were successfully synthesized on microscale and macroscale radiochemical protocols. The biodistribution of [18F] 4-N-alkyl gemcitabine analogue was analyzed via PET imaging. The cytotoxicity activity of the silane gemcitabine analogues were studied in cancer L1210 and HEK293 cell lines and their cellular uptake were investigated using HPLC analysis and fluorescence microscopy.

Reduction of ribono-1,4-lactones and gulono-1,4-lactone as well as ribono-1,5-lactone and glucono-1,5-lactones with LTBH (1.2 equiv.) in CH2Cl2 at 0 °C for 30 min provided the corresponding pentose or hexose hemiacetals in chemoselective fashion and in high yields. Commonly used in carbohydrate chemistry protecting groups such as trityl, benzyl, silyl, acetals and to some extent acyls are compatible with this reduction.

Identifier

FIDC001927

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