Mechanism of DNA Binding and Cleavage

Biomedicine and Biotechnology, 2014, Vol. 2, No. 1, 1-9

Available online at http://pubs.sciepub.com/bb/2/1/1

DOI:10.12691/bb-2-1-1

Sangeetha Gowda K.R.

, Blessy Baby Mathew

, C.N. Sudhamani

, H.S. Bhojya Naik

1,*

Department of Studies and Research in Industrial Chemistry, School of Chemical Sciences, Kuvempu University, Shankaraghatta, India

Department of Biotechnology, Sapthagiri College of Engineering, Bangalore, India

*Corresponding author: hsb_naik@rediffmail.com

Received November 14, 2013; Revised December 11, 2013; Accepted December 26, 2013

Abstract The necessity for cellular regulation of DNA led to the development of metallonucleases to catalyze and

repair DNA strand breaks. Due to cationic character, three-dimensional structural profiles, and propensity for

performing hydrolysis, redox, or photoreactions of metal ions and complexes, have a natural ability for interacting

with DNA. Since binding and cleavage of DNA is at the heart of cellular transcription and translation, it is an

obvious target for therapeutic intervention and the development of diagnostic structural probes. Inorganic constructs

such as cisplatin and its analogs exercise antitumor activity by inner-sphere coordination to DNA. During the last

decades, the continuous evolution of artificial metallonucleases and metal-based chemotherapeutics such as cisplatin,

photo-active octahedral metal complexes have been successfully used as DNA luminescent probes and light-driven

reactive agents during the last decades. A recent emerging trend to improve their potential as molecular tools for

studies of the genetic material is the design of bifunctional assemblies where the photo-active metal centre is

tethered through a flexible linker to a nucleic acid recognition or reactive moiety. In this view, new metal complexes

have been designed that utilize or create open coordination positions for DNA binding and hydrolysis, generate

reactive oxygen containing species or other radicals for DNA oxidation, or perform direct redox reactions with DNA.

This review briefly covers the aspects of drug molecule interaction factors, modes of DNA binding via groove

binders, intercalators and alkylators along with the cleavage patterns such as hydrolytic, oxidative and photoinduced

DNA cleavage, taking an example of Cisplatin and its mechanism.

Keywords: DNA, DNA binding, DNA cleavage, DNA drug interaction

Cite This Article: Sangeetha Gowda K.R., Blessy Baby Mathew, C.N. Sudhamani, and H.S. Bhojya Naik,

“Mechanism of DNA Binding and Cleavag.” Biomedicine and Biotechnology 2, no. 1 (2014): 1-9. doi:

10.12691/bb-2-1-1.

1. Introduction

Deoxyribonucleic acid (DNA) is of high biological

significance [1]. DNA has information stored in it in the

form of genes and these are extremely important for

various functions. DNA is the primary target molecule for

most anticancer and antiviral therapies according to cell

biology. Investigations on DNA interactions with

transition metal complexes, especially for those containing

multidentate aromatic ligands, have aroused considerable

interests owing to their potential applications as new

therapeutic agents and interesting properties that make

them as possible probes of DNA structure and

conformation [2,3]. Binding of peptides, small organic

and inorganic molecules to DNA will interfere with a

number of processes like transcription and replication

[4].

By considering this principle various disorders like cancer,

cystic fibrosis etc can be cured by using DNA as targets

for drugs. And with this emerges a whole new topic if

study called DNA drug interaction, which is of great

topical importance since 1960

[5]. Ever since then a lot of

research has happened in finding a number of metal ions

and metal complexes which have been effective in the

cancer treatment. Cleavage of DNA can be achieved by

targeting its basic constituents like base and/or sugar by an

oxidative pathway or by hydrolysis of phosphoester

linkages. Among the host of DNA-binding and cleaving

agents reported so far, transition metal complexes are of

relevance to the present work. Metal complexes have been

found to be potential to bind DNA through multitude of

interactions and to cleave the duplex by virtue of their

intrinsic chemical, electrochemical and photochemical

reactivities. Continuous demand for new anti-cancer drugs

has stimulated chemotherapeutic research based on the use

of metals since potential drugs developed in this way may

be less toxic and more prone to exhibit anti-proliferative

activity against tumors [6,7]. Transition metal complexes

have been extensively studied for their nuclease like

activity using the redox properties of the metal and

dioxygen to produce reactive oxygen species to promote

DNA cleavage by direct strand scission or base

modification [8]. Use of metal nanoparticles can be in

particular advantageous in generating singlet oxygen

[9,10]. A recent report by Geddes and coworkers

demonstrated that the presence of metal nanoparticles can

enhance singlet oxygen generation [11]. The enhanced

electromagnetic fields in proximity to metal nanoparticles

are the basis for the increased absorption and various

computational methods are available to predict the extent

of absorption and the relative increase in singlet oxygen

2 Biomedicine and Biotechnology

generation from photosensitizers [12,13]. DNA is

preferred to be used as target since its 3D structure makes

it easy to locate binding sites for the drug and to detect

changes in conformation resulting from the drug binding.

It is easy to predict the accessible chemical functional

groups for drug binding and it also has the ability to react

with a broader range of chemical species that include

water, metal ions and their complexes.

2. Mechanism

The different ways in which a drug molecule can

interact with the DNA are:

• Through control of transcription factors: Here the

drug molecule doesn’t directly interact with the DNA

instead it will interact with the protein that binds to

the DNA molecule and hence altering the functions.

• Forming DNA-RNA hybrids: By binding to RNA

molecule that in turn binds to single stranded DNA

forming DNA-RNA hybrids which will interfere with

the transcription activity.

• Direct binding of molecules: Here the small

aromatic ligand molecules directly bind to the DNA

double helix and these molecules are of many types

like groove binders, intercalators etc.

Figure 1. DNA structure and its grooves

Steps in drug development for the target DNA molecule

are:

• Based on the knowledge of the DNA of the disease

causing micro organism we can isolate specific

sequences of DNA that are of functional importance

to the organism. For example, in malaria causing

parasite P. falciparum 3 such sequences were

identified and they are TGCATGCA, GTGTCACAC

& GCACGCGCTGC.

• Drugs are then designed to bind to these target

sequences.

• The drug should be sufficiently reactive in order to

bind to the biological target but not so reactive that it

gets deactivated by the other bio molecules in its way

[14]

• The frequency with which these sequences occur in

humans are determined so that the interaction doesn’t

tamper with the normal functions of humans.

DNA-drug interaction generally occurs in two steps, i.e.

binding and cleavage.

2.1. DNA Binding

The interaction of metal complexes with DNA is a

thriving area of research since discovery of cis platin 40

years ago.cis platin when binds to DNA generates

intrastrand crosslink’s that kinks the DNA structure,

inhibits transcription leading to death of cancerous cells.

Intercalation was first proposed by Leeman et.al [15] and

is defined as insertion between base pairs.

Recently, some transition metal complexes having

different ligands such as dipyridoquinoxaline or NSO-

donor Schiff base have been reported, which shows

efficient DNA binding and cleave DNA on visible light –

irradiation [16].

The larger aromatic ring system was

proved to account for the higher affinity for DNA and

consequently for higher antitumor and photocleaving

activities [17]. DNA binding and optical properties have

recently been grafted into a single molecular construct

toward the development of multifunctional

supramolecular complexes. For eg. Ru(II)/ Pt(II)

bimetallic polyazine bridging ligand (BL) structures of the

form [(tpy)RuCl(BL)PtCl2]PF. It possess optical

properties associated with the Ru(II)-polyazine scaffold

and labile chloride ligands at the Pt(II) center analogous to

cisplatin [6,18].

In this process as the name suggests the drug molecule

binds to the DNA at different positions and bind by

forming different bonds such as covalent or non covalent

bonds. Drug–DNA interactions can be classified into two

major categories, intercalation and groove binding.

2.1.1. Groove Binders

These molecules usually place themselves on the minor

groove. These bind with direct interaction with the edges

of base pairs in either of the major (G-C) or minor (A-T)

grooves of nucleic acids. Groove binding does not induce

large conformational changes in DNA and may be

considered similar to standard lock-and-key models for

ligand–macromolecular binding. Groove binders are

usually crescent-shaped molecules that bind to the minor

groove of DNA [19]

The way they interact can be explained as follows:

• Groove binding molecules are usually constructed of

a series of heterocyclic or aromatic hydrocarbon

rings that possess rotational freedom. This allows the

molecule to fit into the minor or major groove, with

displacement of water.

• The drug molecule first identifies targets which are

the specific DNA sequences.

• These targets are in the range of 16 to 18 base pairs.

• Molecules are bonded to the helical structure via non

covalent bonds.

• Groove binders interact with base pairs edges in

either major or minor grooves.

Biomedicine and Biotechnology 3

Figure 2. Adsorption of the complex in the DNA grooves [20]

Most of the drugs are groove binders as the minor and

major grooves provide a tight fit to the drug which binds

to it. As discussed earlier they are of two types, such as

minor groove binders and major groove binders [21]. A

series of heterocyclic or aromatic hydrocarbon rings get

together to form minor groove binding molecules. This

allows the displacement of water and the molecule fits

into the minor groove. The strand backbones are closer

together on one side of the helix than on the other. The

minor groove occurs where the backbones are close

together while the major groove occurs where the

backbones are far apart. It is easier for certain DNA

binding proteins to interact with the bases (the internal

parts of the DNA molecule) on the major groove side

because the backbones are not in the way. On the opposite

sides, the grooves twist around the molecule and certain

proteins bind to DNA to alter its structure or to regulate

transcription or replication [1]. Distamycin and netropsin

are natural products possessing amido groups and three

and two N-methylpyrrole rings. By means of hydrophobic

interactions and hydrogen bonding, distamycin and

netropsin interact with AT-rich regions of DNA in the

minor groove. The terminal amidine group of the small

molecule is basic in nature and attracts the drug molecule

to the negatively charged DNA phosphodiester backbone.

The 2-amino group of guanine confers AT-selectivity on

the drug molecule, preventing distamycin from binding to

the minor groove of G·C base pairs by steric hindrance.

Lexitropsins

A series of dimers and trimers of distamycin and

netropsin have been synthesized and studied to increase

the DNA binding region from 3 base pairs to 10 base pairs

or more.

Dervan polyamides

Above discussed molecules do not have the ideal

crescent shape to wrap around the minor groove of DNA,

and they fail to recognize longer stretches of DNA. So a

series of oligomeric "hairpin" polyamide molecules

containing pyrrole and imidazole ring systems were

synthesized that were able to bind side-by-side in the

minor groove of DNA with high affinity and in a

sequence-specific manner [22].

2.1.2. Intercalators

Figure 3. Intercalation of a planar ligand of the complex in the DNA base pairs stack [27]

Intercalation involves the insertion of a planar molecule

between DNA base pairs, which results in a decrease in

the DNA helical twist and lengthening of the DNA [20].

They consist of planar heterocyclic groups that stack

between adjacent DNA base pairs. The complex one is

stabilized by π-π stacking interactions between the DNA

bases and drug. Intercalators show strong structural

perturbations in DNA [23].

Certain flat aromatic or

4 Biomedicine and Biotechnology

heteroaromatic molecules can fit in between the base pairs

of DNA (intercalate) and stabilize the duplex without the

disruption of base pairing pattern. Intercalation can

lengthen the duplex by around 3 Å per bound drug

molecule, causing unwinding of DNA. This prevents

DNA replication and transcription by interfering with the

action of topoisomerases. The degree of unwinding

depends on the arrangement of the intercalating molecule

and the site of intercalation. The tight ternary complex

created between the intercalated drug, the DNA and the

topoisomerase is toxic to proliferating cells, so

intercalators are often more lethal to cancer cells than to

normal cells. DNA intercalators are used in structural

studies and antisense work. Such as in the incorporation of

acridine into oligos is striking for antisense applications,

since the intercalation of acridine into the DNA-RNA

duplex significantly increases the Tm and thereby

enhances duplex stability without affecting target

specificity [24,25,26].

Acridines

They have its origin from the aniline dye industry. One

of its examples is Proflavine which contains amino groups

that interact with the negatively charged phosphates

groups on DNA due to the presence of ions, whilst the

aromatic ring arrangement intercalates.

Polypeptides

Actinomycins (polypeptide antibiotics isolated from

Streptomyces strains) by blocking chain elongation,

hinder both DNA synthesis and RNA synthesis. They

interact with G·C base pairs as they have need of the 2-

amino group of guanine for binding. The phenoxazone

ring slides into the double helix and intercalates, while the

pentapeptide side chains intermingle with the DNA minor

groove by hydrogen bonding and hydrophobic interactions.

The result of these two mechanisms of interface between

small molecule and DNA (intercalation and minor-groove

binding) is a very steady complex.

Anthracyclines

They can form antitumour antibiotics such as

doxorubicin (adriamycin) and daunorubicin (daunomycin).

Both possess an amino group on the sugar which, when

protonated, forms an ionic interaction with the negatively

charged DNA phosphate backbone. This bond helps to

hold the molecule in place, allowing the planar aromatic

ring system to slide into the double helix. Although

doxorubicin and daunorubicin differ by only one hydroxyl

group, they have different activities. Daunorubicin is

active only against leukaemia, but doxorubicin is active

against leukaemia and also a wide range of solid tumours.

2.1.3. Alkylators

Strong electrophilic compounds that react chemically

with nucleophilic groups on DNA to form covalent bonds

are known as alkylators. The resultant DNA adducts

which are produced are irreversible inhibitors of

transcription and translation. Nucleophilic substitution

reactions at the DNA bases occur by both SN1 and SN2

mechanisms. The most reactive sites are those that are

both nucleophilic and uncovered in the grooves of the

DNA duplex. The N(7) atom of guanine and the N(3)

atom of adenine complete both criteria’s. Simple

nucleophiles, for example ethyleneimines and methane

sulfonates, tend to react through a SN2 mechanism,

whereas the nitrogen mustards can form aziridinium ions

that react through an SN1 mechanism.

Ethyleneimines (aziridines)

Ethyleneimines are pre-formed aziridines and as a

result constitute a natural addition of nitrogen mustards

(mechanism of action of the mustards begins with the

formation of an electrophilic aziridinium ion by

displacement of chloride). To ensure antitumour activity,

at least two ethyleneimine groups must be available in the

molecule. To prevent protonation of the ethyleneimine,

electron-withdrawing groups are attached (protonated

ethyleneimines are too reactive). Lipophilic

ethyleneimines are intended to enter the central nervous

system.

Platinum complexes

Cisplatin and carboplatin stand for a group of anti-

cancer agents used in the treatment of testicular and

ovarian tumours. Cisplatin and carboplatin form sturdy

platinum-nitrogen bonds with guanine and adenine bases.

The cis configuration form intra-strand cross-links which

leads to unwinding of the helix, preventing transcription

and leading to cell death. The trans-isomer, trans-platin, is

not an active anti-cancer agent, perhaps because it cannot

eagerly form intra-strand cross-links. It tends to cross-link

separate strands and such lesions are repaired easily [22].

Table 1. DNA alkylating agents [28]

Alkylating agents Examples

DNA -targeted

mustards

• Oilgopyrrole and oligoimidazole carriers

• Bis-(benzimidazole) carriers

•

Polybenzamide carriers

• 9-Anilinoacridine-4-carboxamide carriers

Guanine-specific

alkylating agents

• Mitomycins

• Carmethizole analogues

•

Pyrrolobenzodiazepines

•

Ecteinascidin analogues

Adenine-specific

alkylating agents

• Duocarmycin and analogues

• Benz[e]indolones

• Analogues of KW-2189

•

Amino analogues

• Bizelesin and other bis analogues

2.2. DNA Cleavage

Cleavage of DNA is a vital process in all living systems.

For example, topoisomerase enzymes resolve topological

problems of DNA in replication, transcription and other

cellular transactions by cleaving one or both strands of the

DNA [25]. Another example are restriction enzymes (or

restriction endonucleases), which protect the cell against

virus infection by cleavage of the foreign DNA [29], or by

degrading cellular DNA during apoptosis of the affected

cell

[30]. Finally, the activity of many anticancer drugs

rely on their ability to introduce extended damage to the

DNA in the (affected) cells (e.g. bleomycin) [31], which

can trigger apoptosis [32], leading to the cell death [33]. In

general, three different types of DNA cleavage can be

distinguished, namely i) DNA hydrolysis, ii)

photochemical cleavage, and iii) oxidative cleavage,

although the last two categories are quite closely related.

2.2.1. Hydrolytic Cleavage

It can be defined as a method of DNA cleavage by the

cleavage of phosphor diester bonds to generate fragments

in the presence of water. The fragments produced here can

be relegated. The half life of a typical phosphate diester

bond of DNA in neutral water under ambient conditions

Biomedicine and Biotechnology 5

(25°C) is estimated to be in the order of tens to hundred

billions of years. This means that a catalyst has to

accelerate this reaction 1017-fold to achieve an effective

hydrolysis of the phosphate backbone of DNA within an

acceptable timeframe (i.e. a couple of min). General

mechanism of this method is the hydrolysis reaction is

facilitated by the presence of metal ions, acting as Lewis

Acids. These Lewis acids can activate the phosphate

group towards nucleophilic attack, activate water or

hydroxide as nucleophile or increase the leaving group

ability of the departing alcohol. The general accepted

mechanism of the DNA hydrolysis reaction is a

nucleophilic attack at the DNA phosphate backbone, to

form a five coordinate intermediate, which can be

stabilized by the catalyst. Subsequent cleavage of either

the 3’-PO (as seen is most often in enzymatic systems) or

the 5’-PO results in a strand scission. After this

nucleophillic attack one group leaves as an alcohol.

Figure 4. Proposed reaction mechanism for the hydrolysis of DNA

Figure 5. Cleavage at nucleobases

2.2.2. Oxidative Cleavage

This method of cleavage involves the oxidation of

deoxy ribose by abstraction of sugar hydrogen or

oxidation of nucleobases. Oxidative cleavage is usually

mediated by the presence of additives and photo induced

DNA cleaving agents i.e. an external agent like light or

is required to initiate cleavage. Like in hydrolytic

cleavage in this method the DNA fragments cannot be

religated. Oxidative cleavage can occur both at the

carbohydrate level and at the nucleic base level. Oxidative

cleavage of DNA can result in the damage of all four

nucleobases or the deoxy ribose sugar. Generally

Hydroxyl radical species of O

(OH) are involved in this

oxidative cleavage. The mechanism of oxidative cleavage

occurs in 3 ways: hydrogen abstraction, addition and

electron transfer.

Cleavage at deoxyribose sugar: If the oxidative

cleavage occurs

at the carbohydrate, abstraction of one

hydrogen of deoxyribose can initiate the oxidative

cleavage process. In the next figure the process following

the C-3’ abstraction of deoxyribose is shown in Figure 5.

The

oxidation at the nucleic base level occurs

preferably at

guanine because it’s lower oxidation

potential. Hydroxyl radical reacts with the heterocyclic

bases in DNA by addition. In pyramidines OH adds to the

C5 or C6 double bond leading to cleavage. In purines the

hydroxyl ion binds to the C4, C5 & C8

[34].

2.2.3. Photoinduced DNA Cleavage

Photocleavage of nucleic acids allows the use of light to

trigger nuclease activity. Nucleases that are activated by

visible or near-UV light can be used for examination of

processes such as transcription and to probe nucleic acid

structure as photofootprinting and photo-sequencing

agents.On the other hand, photosensitization of DNA by

drugs may be useful as a potential anti-tumor therapy.

DNA photocleavage can occur by a wide variety of

mechanisms such as [35] hydrogen atom abstraction from

the sugar ring by photochemically generated radicals [36],

direct electron transfer from the base (usually guanine) to

the photoexcited cleaver [37], singlet oxygen production

by transfer of energy from the excited photocleaver, and

[38] formation of base adducts.

DNA damage initiated by photosensitization can be

divided in two major types; Type I process a one electron

process and Type II process a pathway involving singlet

oxygen [39,40].

In the first type (Type I process), the cleaving agent is

excited and generates sequentially a superoxide radical

from molecular oxygen via an electron transfer step.

Superoxide itself is a rather poor oxidant [41], and it can

be further reduced (leading to H

and OH) or it can

function as a reductant. The DNA damage observed via

this pathway is mainly guanine oxidation, formed via

guanine radical cations [39,40]. This results in the

formation of base labile sites in the DNA.

In a Type II process, the photo excited compound

generates singlet oxygen, which only modifies guanine

6 Biomedicine and Biotechnology

residues, in contrast to superoxide. Two pathways can be

distinguished [39,40,42,44] A Diels-Alder reaction with

singlet oxygen results in the formation 4,8-dihydro-4-

hydroxy-8-oxo-dG, and after further reduction in 8-oxo-

dG. A [2+2] cycloaddition with singlet oxygen results

after a cascade of reactions in the formation of cyanuric

acid. The modified residues are base labile positions in the

DNA and alkaline.

Figure 6. Names and structures of selected photosensitizers in clinical or pre-clinical studies

Figure 7. Schematic representation of PDT mechanism

2.3. Cisplatin a Classical Example of DNA

Binding and Cleavage Agent

The inorganic compound cis-

diamminedichloroplatinum (II) cis-[Pt(NH

)

(Cl)

]

commonly referred to as cisplatin, also called as Peyrone's

salt was named after Michel Peyrone who first synthesized

it in 1845. It was the first member of a class of platinum-

containing anti-cancer drugs, which now also includes

carboplatin and oxaliplatin. Cisplatin and its analogs are

heavy metal complexes containing a central atom of

platinum surrounded by two chloride atoms and two

ammonia molecules in the cis position. Cisplatin is a

white lyophilized powder soluble in water or saline at

1mg/ml and in diethylformamide at 24 mg/ml with a

melting point of 270°C. Cisplatin has biochemical

properties similar to that of bifunctional alkylating agents,

producing interstrand, intrastrand and monofunctional

adduct cross-linking in DNA.

Biomedicine and Biotechnology 7

2.3.1. Mechanism of Cisplatin

One chloride ligand is slowly displaced by water

resulting in the formation of [PtCl (H

O)(NH

)

] [16].

Because of this the complex can bind to bases easily

especially to guanine [PtCl (guanine-DNA) (NH

)

]

. On

displacement of another Chlorine molecule by water the

cisplatin molecule can bind to another guanine in the same

DNA molecule forming a cross link between the two

strands. After complete binding of the Cisplatin the DNA

molecule will bend at a 30 deg. Angle. This leads to DNA

damage. The damaged DNA elicits DNA repair

mechanism which leads to apoptosis.

Table 2. DNA Cleavage agents

Types of

cleavage

Examples References

Hydrolytic

cleavage

Cu(II)TACH complex

copper-ATCUN complexes

copper(II)−l-histidine complex

[CoII(CysGly)(HisSer)]

[CoII(CysGly)(HisPhe)]

[45]

[46]

[47]

[48]

Oxidative

cleavage

Zn(F-BDPA)(NO3)2

[Cu(mbpzbpy)Br2](H2O)2.5

[Cu(mpzbpya)Cl](CH3OH)

[Cu2(mTPXA)Cl4]3 H2O

[Cu2(pTPXA)Cl4]3 H2O

[Cu3(HPTAB)Cl5]Cl3 H2O

[49]

[50]

[51]

Photo induced

cleavage

(photosensitizers)

Photofrin® (HpD)

Levulan® (ALA)

Metvix® (M-ALA)

Visudyne® (Vertiporfin)

Antrin® (Lutexaphyrin)

Foscan® (Temoporfin)

LS11 (Talaporfin)

Photosens® (Phthalocyanine)

[52]

Cisplatin is administered intravenously as short-term

infusion in normal saline for treatment of solid

malignancies. It is used to treat various types of cancers

like ovarian, bladder, cervical, lungs etc.

Figure 8. Mechanism of Cisplatin [53]

3. Conclusion

Recent advances in medicinal inorganic chemistry

demonstrate significant prospects for the utilization of

metal complexes as drugs, presenting a flourishing arena

for inorganic chemistry. Compounds containing metal

ions have and will continue to play an important role in

biomedical technology. Whether as imaging agents,

therapeutics or probes for chemical genetics, inorganic

compounds will continue to provide the research

community with tools that cannot be achieved with

organic chemistry alone. Significant progress in platinum

based anticancer agents has been achieved, based in part

on a mechanistic understanding of the DNA-binding and

pharmacological effects of cisplatin. Several new

compounds with reduced toxicity and high specificity

have been developed. Ruthenium complexes with

antitumor activity are also emerging rapidly. The future

development of medicinal inorganic chemistry requires an

understanding of the physiological processing of metal

complexes or drugs with DNA, to provide a rational basis

for the design of new metal-based drugs. In this direction

of designing new drugs understanding the mechanism of

DNA drug interaction is vital. Application of new

methodologies such as combinatorial chemistry,

extensively used in organic drug discovery, will be

beneficial for the development of inorganic compounds as

therapeutics.

Abbreviations

TACH: 1,3,5-triaminocyclohexane

ATCUN: amino terminal copper nickel

CysGly: cysteinylglycine

HisSer: histidylserine

HisSer: histidylphenylalanine

BDPA: N,N′-bis(benzyl)-N,N′-bis(2-

pyridylmethyl)-6,6′-bis(aminomethyl)-

2,2′-bipyridine)

mbpzbpy: 6,6-bis(3,5-dimethyl-N-pyrazolmethyl)-

2,2-bipyridine)

Hmpzbpya: 6-(3,5-dimethyl-N–pyrazolmethyl)-2,2-

bipyridine-6-carboxylic acid)

mTPXA: N,N,N',N'-tetra-(2-pyridylmethyl)-m-

xylylene diamine

pTPXA: N,N, N',N'-tetra-(2-pyridylmethyl)-p-

xylylenediamine

HPTAB: N,N,N',N',N'',N''-hexakis(2-

pyridylmethyl)-1,3,5-tris-

(aminomethyl)benzene

HpD: Hematoporphyrin derivative

ALA: 5-Aminolevulinic acid

M-ALA: Methylated 5-Aminolevulinic acid

BPD: Benzoporphyrin derivative

LS11: talaporfin Sodium.

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