Identifier

etd-11212005-190249

Degree

Master of Science (MS)

Department

Chemistry

Document Type

Thesis

Abstract

In oncologic applications of photodynamic therapy (PDT), the discriminating localization of porphyrin-type compounds in solid tumors is exploited for the selective ablation of neoplastic tissue with minimal destruction and irritation to normal tissue. PDT is a locoregional, binary cancer therapy in which a photosensitizer—light-activated drug—absorbs light of an appropriate wavelength and excites to the singlet state. This photosensitizer in the excited singlet state can undergo an internal transition to the excited triplet state, a relatively long-lived and high-energy species that transfers its excess energy to molecular oxygen. Molecular oxygen subsequently excites from the stable triplet state to the highly reactive singlet state. With no spin-state restriction, singlet oxygen is cytotoxic, readily reacting with electron-rich biomolecules such as unsaturated lipids, amino acids and DNA consequently destroying the tumor cell. Singlet oxygen has a limited range of diffusion. Therefore, the site of its generation is also the site of initial damage. Mono-L-aspartyl chlorin e6, a chlorophyll a derivative also known as talaporfin and subsequently referred to here as NPe6, is a 2nd-generation photosensitizer currently in advanced-stage clinical trials for PDT. NPe6 is obtained by transesterification of the phytyl ester group of chlorophyll a with a methyl ester group to form pheophorbide a. Subsequent isocyclic ring opening forms chlorin e6 trimethyl ester. Alkaline hydrolysis of the methyl esters and then activation and coupling to a protected aspartic acid followed by deprotections yields NPe6. The structural elucidation of NPe6 has been performed employing a classical methodology of an unambiguous synthesis used adjunctively with modern NMR techniques. The synthesis of NPe6 has been made more efficient via the optimization of the isocyclic ring opening and coupling reaction. Natural reactivities of chlorophyll a derivatives have been exploited to synthesize two regiosomers of NPe6 for biological property investigation. A novel route to a 173 chlorin e6 derivative has been generated. Because to date no chlorin photosensitizers have received FDA approval in the United States, various amino-acid porphyrin conjugates- specifically PPIX conjugates- have been synthesized and their preliminary biological evaluation, which demonstrates that subtle differences in structure can correlate to huge differences in function, is described.

Date

2005

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Maria da Graca H. Vicente

DOI

10.31390/gradschool_theses.416

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