BORDİPİRİN (BODIPY) BİLEŞİKLERİ KİMYASI VE UYGULAMALARI

1. 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

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

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

4. Bilkent University Our First Encounter with Bodipy

5. Bilkent University Reverse PET/Bipyridyl-Bodipy

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

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

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

9. Bilkent University Nanotechnology Takes Aim at Cancer

10. Bilkent University Dendrimers as versatile platforms

11. 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.

12. Bilkent University Meyer-Betz: experiment on self

13. 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 Bilkent University Practice of Photodyamic Therapy

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

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

16. Bilkent University Light penetration in mammalian tissues

17. Bilkent University Enhanced permeation and retention- EPR

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

19. Bilkent University PDT: How the tumor dies

20. 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

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

22. 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

23. 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)

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

25. Bilkent University Boradiazaindacene based PDT reagents

26. TARGET PHOTOSENSITIZER Enhanced solubility in aqueous media The presence of heavy atomsprovides enhanced intersystem crossing Long wavelengthabsorption (650-680 nm)

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

28. 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 anincubator. 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.