BORDİPİRİN (BODIPY) BİLEŞİKLERİ KİMYASI VE UYGULAMALARI Engin Umut Akkaya Bilkent Üniversitesi, Kimya Bölümü & UMAM-Malzeme Bilimi ve Nanoteknoloji Enstitüsü 06800 Ankara E-mail: eua@fen.bilkent.edu.tr

Bodipy: A versatile chromophore Bilkent University Bodipy: A versatile chromophore Ion Sensing Photodynamic Therapy Solar Cells Molecular Logic Gates Energy Transfer Cassettes Liquid Crystals Light Harvesting systems DNA Labeling 2 2

Derivatization of the BODIPY core Bilkent University Derivatization of the BODIPY core Ziessel Boens Rurack & Daub Akkaya 8 2 3 5 7 6 4 1 Burgess Akkaya(2009)

Our First Encounter with Bodipy Bilkent University Our First Encounter with Bodipy

Reverse PET/Bipyridyl-Bodipy Bilkent University Reverse PET/Bipyridyl-Bodipy

EET Moleküler Algılayıcısının Modüler Tasarımı Coşkun, A.; Akkaya, E. U. J. Am. Chem. Soc. 2005, 127, 10464.

Modulation of EET via cation binding Bilkent University Modulation of EET via cation binding Coskun, A.; Akkaya, E. U. J. Am. Chem. Soc., 2006, 128, 14474-14475

Donör gruptan enerji aktarımının modülasyonu Exc@580 Ems@670 Hg Guliyev, R.; Coskun, A.; Akkaya, E. U. J. Am. Chem. Soc., 2009, 131, 000.

Nanotechnology Takes Aim at Cancer Bilkent University Nanotechnology Takes Aim at Cancer

Dendrimers as versatile platforms Bilkent University Dendrimers as versatile platforms

A very brief history of photodynamic therapy Bilkent University A very brief history of photodynamic therapy Oscar Raab/von Tappeiner (1900) A particular dye (acridine)+ Light, kills aquatic organisms. Jodlbauer/von Tappeiner (1904) “photodynamische wirkung” oxygen is also required for activity Meyer-Betz (1912) Demonstration of photodynamic activity in human. 200 mg hematoporphyrin (redness and oedema) Porphyria connection High concentration levels of protoporphyrin in plasma. FDA approval (1995) Photophyrin was approved for esophogal cancer.

Meyer-Betz: experiment on self Bilkent University Meyer-Betz: experiment on self

Practice of Photodyamic Therapy Bilkent University Practice of Photodyamic Therapy In December 1995, the FDA approved a photosensitizing agent called porfimer sodium (Photofrin) combined with light from a laser for treating patients with cancer of the esophagus in the following situations: To relieve symptoms of esophageal cancer, including difficulty swallowing, that are caused by a tumor obstructing (blocking) the esophagus To treat esophageal cancer that cannot be treated with laser therapy alone In 1998, the FDA approved porfimer sodium for two additional uses: To treat endobronchial (affecting the lining of the bronchi) non-small cell lung cancer that is microinvasive (has minimal spread of cancer cells) for patients who cannot have other types of treatment such as surgery or radiation therapy To reduce obstruction and to palliate (ease) symptoms in people with endobronchial non-small cell lung cancer that is either completely or partially obstructing the bronchi

From “Scientific American, January 2003* Bilkent University From “Scientific American, January 2003* * New Light on Medicine

The Jablonski diagram Bilkent University http://www.monos.leidenuniv.nl/smo/index.html?basics/photophysics.htm

Light penetration in mammalian tissues Bilkent University Light penetration in mammalian tissues

Enhanced permeation and retention- EPR Bilkent University Enhanced permeation and retention- EPR

In vivo veritas ! Bilkent University http://www.uphs.upenn.edu/radiology/depa/MICL/MolecularImagingChemistry2.htm

Bilkent University PDT: How the tumor dies

Applications of PDT Potential Cancer Therapy – Endobronchial cancer Bilkent University Applications of PDT Potential Cancer Therapy – Endobronchial cancer – Esophageal cancer – Skin Cancers – Breast Cancers – Colorectal Tumors – Gynecologic malignancies Other Diseases – Cardiovascular (e.g., alternative to angioplasty) – Chronic skin diseases [e.g. Psoriasis (in development)] – Autoimmune (e.g. Rheumatoid arthritis) – Macular degeneration – Antibacterial (wound healing, oral cavity) – Vaccine – especially anticancer vaccines – Endometriosis – Precancerous conditions

The light activated drugs in the market or in development Bilkent University The light activated drugs in the market or in development

Ideal photosensitizer for PDT Bilkent University Ideal photosensitizer for PDT is a chemical compound that can be excited by light of a specific wavelength A good photosensitizer should have: Little or no toxicity in the dark Good pharmokinetic behaviour (high selectivity for tumour tissue and easy elimination from the body) A constant composition (preferably a single achiral substance) A high triplet quantum yield and a triplet energy with efficient energy transfer to produce singlet oxygen And red absorption to take advantage to deep light penetration

Dyes with known sensitizer activity Bilkent University Dyes with known sensitizer activity Quinone derivatives : Hypericin (590 nm), Acriflavin (460 nm). Acridine dyes: Acridine Orange (492 nm) Phenothiazine: Methylene blue (660 nm) Xanthene dyes: Rose Bengal (549 nm) Cyanine dyes: merocyanine (540 nm) -Porphyrins, Chlorins and Bacteriochlorin: Hematoporphyrin (645 nm) -Phthalocyanines: Phthalocyanine (698 nm), tetra-t-butylnaphthocyanine (784 nm)

Red light activation of the sensitizer Bilkent University Red light activation of the sensitizer Filtered red light l> 600 nm (2005) Red LED array l= 625 nm (2006)

Boradiazaindacene based PDT reagents Bilkent University Boradiazaindacene based PDT reagents

TARGET PHOTOSENSITIZER Enhanced solubility in aqueous media The presence of heavy atoms provides enhanced intersystem crossing Long wavelength absorption (650-680 nm)

Degradation of the singlet oxygen trap Bilkent University Degradation of the singlet oxygen trap with 9 nM sensitizer

Standard MTT assay of photoinduced Bilkent University Standard MTT assay of photoinduced cytotoxicity Percent viability as determined by a standard MTT assay. “Control” corresponds to assay data obtained with K562 cells kept in full medium in dark at 37 oC in an incubator. The other black bars show cell viability at different sensitizer concentrations in dark. Red bars show percent viability at the indicated concentrations under 4 hr irradiation with red LED at 2.5 mW/cm2 fluence rate, followed by 20 hr incubation in dark at 37oC. Percent viability values shown here are the averages of 4 runs.