BORDİPİRİN (BODIPY) BİLEŞİKLERİ KİMYASI VE UYGULAMALARI

Engin Umut Akkaya Bilkent Üniversitesi, Kimya Bölümü &UMAM-Malzeme Bilimi ve Nanoteknoloji Enstitüsü06800 Ankara

E-mail: eua@fen.bilkent.edu.tr

Ion Sensing Photodynamic Therapy

Solar Cells Molecular LogicGates

Energy Transfer

Cassettes Liquid Crystals

Light Harvestingsystems

DNA Labeling

Bodipy: A versatile chromophoreBilkent University

Ziessel

Boens

NB

N

H3C

H3C

CH3

CH3F F

Rurack & Daub

AkkayaAkkaya

8

2

35

7

6

4

1

Burgess

Derivatization of the BODIPY coreBilkent University

Akkaya(2009)

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Our First Encounter with Bodipy

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Reverse PET/Bipyridyl-Bodipy

EET Moleküler Algılayıcısının Modüler Tasarımı

Coşkun, A.; Akkaya, E. U. J. Am. Chem. Soc. 2005, 127, 10464.

n = 2

n = 4

ref. F600/F700 = 2.8

F600/F700 = 5.9

F600/F700 = 7.2

nLD A

nLD A Hg2+

h @ 500 nm

h @ 500 nm

EET

Larger EET

h @ 700 nm

h @ 600 nm

nLD A

nLD A Hg2+

h @ 500 nm

h @ 500 nm

EET

Larger EET

h @ 700 nm

h @ 600 nm

n = 2

n = 4

ref. F600/F700 = 2.8

F600/F700 = 5.9

F600/F700 = 7.2

nLD A

nLD A Hg2+

h @ 500 nm

h @ 500 nm

EET

Larger EET

h @ 700 nm

h @ 600 nm

nLD A

nLD A Hg2+

h @ 500 nm

h @ 500 nm

EET

Larger EET

h @ 700 nm

h @ 600 nm

Coskun, A.; Akkaya, E. U. J. Am. Chem. Soc., 2006, 128, 14474-14475

Modulation of EET via cation bindingBilkent University

Hg

Exc@580

Ems@670

Donör gruptan enerji aktarımının modülasyonu

Guliyev, R.; Coskun, A.; Akkaya, E. U. J. Am. Chem. Soc., 2009, 131, 000.

Nanotechnology Takes Aim at CancerBilkent University

Dendrimers as versatile platforms

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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.

A very brief history of photodynamic therapy

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Meyer-Betz: experiment on self

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

Practice of Photodyamic Therapy

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From “Scientific American, January 2003*

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* New Light on Medicine

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The Jablonski diagram

http://www.monos.leidenuniv.nl/smo/index.html?basics/photophysics.htm

Light penetration in mammalian tissues

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Enhanced permeation and retention- EPR

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http://www.uphs.upenn.edu/radiology/depa/MICL/MolecularImagingChemistry2.htm

In vivo veritas !

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PDT: How the tumor dies

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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

Applications of PDT

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The light activated drugs in the market or in development

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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 andeasy 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

Ideal photosensitizer for PDT

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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)

Dyes with known sensitizer activity

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Red light activation of the sensitizer

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Filtered red light > 600 nm (2005) Red LED array = 625 nm (2006)

NB

N

Me Me

F F

BrBr

R2

YR2 R2 Y

R2

XR1R1

X = R1 = O(CH2CH2O)3CH3Y = Br, R2 = H

X = Br, R1 = HY = R2 = O(CH2CH2O)3CH3

X = R1 = O(CH2CH2O)3CH3Y = R2 = O(CH2CH2O)3CH3

1-3

1

2

3

Boradiazaindacene based PDT reagentsBilkent University

TARGET PHOTOSENSITIZER

Enhanced solubility in aqueous media

The presence of heavy atoms provides enhanced intersystem crossing

Long wavelength absorption (650-680 nm)

N B N

Me Me

F F

OO

O

O

OO

O

O

O

O

O

O

BrBr

O

OOO

OO

O

O

OO

OO

OO

O

O

O

O

O

OO

OO

O

Degradation of the singlet oxygen trap with 9 nM sensitizer

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0

20

40

60

80

100

sensitizer concentration (nM)

pe

rce

nt

via

bilit

y

25 50 100 200 400 500control

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.

Standard MTT assay of photoinduced cytotoxicity

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