Synthesis and evaluation of novel phenazine dyes

for use in PDT

By Amina Tariq

Interest in Dyes PDT: A modern application of photoactive

dyes Project Aims Chemical Strategy Dark and Light Promoted Reactions Reaction Highlights Challenges Future Work References

Outline

NH

O HN

O

O

O

NH2

OH

O

Broad spectrum of applications owing to unique physio-

chemical properties Synthesis of dyes is what revolutionised the synthetic

organic chemistry Cover the full spectrum in particular yellow, red and

oranges/complete rainbow of colours Intense bright colours with good fastness properties Extensively utilised in pharmaceutical, cosmetics, food,

dyeing/textiles, printing and analytical chemistry Medically important as they are well-known for their

antibiotic, antifungal and anti-HIV properties

Interest in dyes

Example of phenazine based dyes

N

N

NHH2N

Mauveine

NH

NH3C

H2N NCH3

CH3

Cl

Neutral red

S

N

NN

Methylene blue

Photoactive – A substance/compound is considered photoactive if it is capable of absorbing light of appropriate wavelength, and as a result of this light absorption undergoes various photochemical and photophysical events mainly Fluorescence and Phosphorescence.

Photodynamic Therapy (PDT)- A type of treatment that involves the use of a light-sensitive medication (photoactive dye) and a source of light to destroy abnormal cells.

PDT: A Modern Application of Photoactive Dyes

N

N NH2N

Project AimsN

N ClN

N

N BrN

N

N INNeutral Red• Triplet-photosensitizer• Photoredox catalyst• Low quantum yield

Targeted compounds

(1)

(3)

(4)

(5)

Chemical Strategy

Diazo component Diazonium salt

Coupling component

N

N NH2N

HClKX

N

NN NN

N

N IN

X = I, Cl, Br

HCl/THFCl

N

N BrN

N

N ClN

(1)(2) (3)

(4)

(5)

NaNO2

N

N NH2N

HClN

NN NN

N

N IN

HCl/H2OCl

N

N ClN(1)

(2)

(3)

(5)

NaNO2

KI

N

NN

(6) (75%)

(15%)

(12%)

Reaction carried out under ambient light/dark conditions

1. Reduced form of the salt is the major product

2. Other side products3. Target compound is in low yield4. Reduced form highly stable/high redox

potential5. High activation barrier

Reaction carried out using a light source

1. Using a light source helps to overcome the activation barrier

2. Reaction goes to completion3. Targeted compound isolated in

good yield4. Reaction is reproducible

N

N NH2N

HClN

NN NN

N

N INHCl/H2O

ClKI

Cl

(1) (2)

LampNaNO2

CuI

N

NN NNBF4

HBF4/H2O

N

NN

(2)

NaNO2

(7) (64%)

(6) (70%)

Instability of “Aryl Diazonium Salt” under RT Determination of the reaction mechanism is

required to establish right conditions

Challenges

Simple and cheap, easy to handle reagents, readily available

Mild reaction conditions No need to use organometallic reagents as

Neutral Red autocatalyses the reaction Low environmental impact due to use of water as

a solvent Easy to scale-up

Reaction Highlights

Study of photo- and electrochemistry of diazonium salt of Neutral Red to understand the mechanistic pathways

Acquire details of photoredox chemistry of participating reagents and intermediates to better understand the kinetics of the reaction

Future Research Plan

CHEMIK 2012, 66, 12, 1298-1307 MUHAMMAD A RAUF, A.A.S., MUHAMMAD KHATTAB. Solvent effects on the spectral properties of Neutral Red. Chemistry Central

Journal, 2008, 2(19). BINDEWALD, E., R. LORENZ, O. HUBNER, D. BROX, D.-P. HERTEN, E. KAIFER and H.-J. HIMMEL. Tetraguanidino-functionalized phenazine

and fluorene dyes: synthesis, optical properties and metal coordination. Dalton Transactions, 2015, 44(7), pp.3467-3485. SINGH, M.K., H. PAL and A.V. SAPRE. Studies on the Radiolytically Produced Transients of Neutral Red: Triplet and Reduced

Radicals. Photochemistry and Photobiology, 2000, 71(1), pp.44-52. WAINWRIGHT, M. Dyes in the development of drugs and pharmaceuticals. Dyes and Pigments, 2008, 76(3), pp.582-589. MARKS, G.T., LEE, E. D., AIKENS, D. A. AND RICHTOL, H. H. TRANSIENT PHOTOCHEMISTRY OF NEUTRAL RED. Photochemistry

and Photobiology, 1984, 39, pp.323–328. WAINWRIGHT, M. Photodynamic therapy – from dyestuffs to high–tech clinical practice. Review of Progress in Coloration and

Related Topics, 2004, 34(1), pp.95-109. MURUBE, J. Rose Bengal: The Second Most Commonly Used Surfocular Vital Stain. The Ocular Surface, 2014, 12(1), pp.14-22. MINGLIANG HAN, X.Z., XIAOXIA ZHANG, CHAOQIANG LIAO, BAIQING ZHU, QIAOLING LI. Azo-coupled zinc phthalocyanines:

Towards broad absorption and application in dye-sensitized solar cells. Polyhedron, 2015, 85, pp.864-873. BONNETT, R. Photosensitizers of the porphyrin and phthalocyanine series for photodynamic therapy. Chemical Society

Reviews, 1995, 24(1), pp.19-33. ANA P. CASTANO, T.N.D., MICHAEL R, HAMBLIN. Mechanisms in photodynamic therapy: part one-photosensitizers,

photochemistry and cellular localization. Photodiagnosis and Photodynamic Therapy, 2004, 1(4), pp.279-293. LASTOVOI, A.P., A.A. IGNATOVA, A.V. FEOFANOV, E.A. MACHINSKAYA and V.I. IVANOVA-RADKEVICH. Properties of the Novel

Photosensitizer β,β,β ,β -Tetramethyltribenzotetraazachlorin. ′ ′ Pharmaceutical Chemistry Journal, 2014, 48(2), pp.77-81.

References

Dr. Natalia SergeevaDr. Terry KeyAna Maria Garrote CanasEllana BeardDepartment of Colour ScienceFaculty of Mathematics and Physical Sciences at University of Leeds

Acknowledgments

Thank you