Synthesis of 5, 10, 15, 20-Tetrakis(7-sulfanatobenzo[b]thiophene) Porphyrin for Mitochondria and DNA Targeted Photodynamic Therapy

Abstract

Porphyrins are rich in applications and it can be called as the colors of life. From the photosynthetic process in plants, to the red hemoglobin that carries oxygen to the cells in our bodies utilize porphyrin molecules. Thus, without any surprise porphyrins are actively explored as tools for wider applications to improve medicine and other biomedical fields. With the aim of improving photodynamic therapy (PDT) in mind, this thesis work examines new synthetic porphyrins for selective targeting of sub-cellular compartments in cancerous cells and execute apoptotic cell death upon PDT, and causing minimal destruction and irritation to normal tissue.

PDT is a phototherapeutic cancer therapy in which a photosensitizer (PS)—light activated drug—absorbs light of specific wavelength and excites to the singlet state. From the excited singlet state, PSs 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. Subsequently, molecular oxygen 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.

Photosensitizers used in PDT are often classified as first, second and third generation PS. This classification is based on the historical development and conceptual approaches. Haematoporphyrin derivative (HpD) or Photofrin are otherwise called as first generation PS enjoyed its success in cancer therapy due to their tumor localizing and photophysical properties yet suffers from its drawbacks (mixture of compounds and less selectivity). Herein, second generation PSs with high purity and improved photophysical properties had been developed. Still there is always room for improver, and current research efforts are aimed at developing third generation PSs where additional biological criteria such as selective targeting of sub-cellular organelles are considered in the design principle.

Herein, this thesis work focused in developing third generation PSs that can target selectively sub-cellular organelles such mitochondria and DNA and effectively induce apoptotic cell death after PDT. In Chapter I, a comprehensive background on history of photodynamic therapy, fundamental aspects, classification and requirements of PSs is presented. In chapter 2, synthesis, structural elucidation, photophysical properties and in vitro photokilling and mechanism of cell death of 5, 10, 15, 20–Tetrakis(7-sulfonatobenzo[b]thiophene)porphyrin (SBTP) is studied.

Keywords: porphyrin

photosensitizers

photodynamic therapy

mitochondria

DNA

apoptosis

intrinsic

extrinsic

high-content assay.

Student number: 2010-31366