ABSTRACT

Transcription and replication are vital for cell survival and proliferation also for smooth

functioning of all body processes. DNA starts transcription or replication only when it receives a

signal, which is often in the form of a regulatory protein that binds to a particular region of the

DNA. So, if the binding specificity and strength of such regulatory protein can be mimicked by a

small molecule, then the DNA function can be artificially inhibited, activated or modulated by

binding the mimicked molecule instead of the protein. Thus, this synthetic/natural molecule can

act as a drug when inhibition or activation of DNA function is required to control or cure a

disease.

DNA inhibition would lead to restriction of protein synthesis, or replication, and could possibly

induce cell death. DNA activation would lead to production of more quantities of the required

protein, or could lead to DNA replication; depending on which site the drug is targeted. Though

both these processes are possible, mostly the DNA is targeted in an inhibitory mode, to destroy

cells for antibiotic and antitumor action.

Drugs can bind to DNA both covalently as well as non-covalently.

Covalent binding in DNA is irreversible and invariably leads to complete inhibition of DNA

processes and subsequent cell death. Cis-platin (cisdiamminedichloroplatinum) is a famous

covalent binder which is used as an anticancer drug, and makes an intra/interstrand cross-link via

the chloro groups with the nitrogens on the DNA bases.

Non-covalent binding is reversible and is typically preferred over covalent adduct formation

keeping the drug metabolism and toxic side effects in mind. However, the high binding strength

of covalent binders serves as a major advantage.

Proteins are large molecules and bind quite strongly to DNA, with binding constants in

nanomolar range. It has been difficult to achieve similar specificity and affinity using small non-

covalent binders, and remains a major challenge to the design of drugs for DNA.

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INTRODUCTION TO DNA

DNA is a natural product, indeed it is a natural product of the paramount importance in

understanding the mechanism of genetic processes, of cell growth and differentiation, of ageing

and senescence. Most of the DNA is located in the cell nucleus (where it is called nuclear DNA),

however a small amount of DNA can also be found in the mitochondria (where it is called

mitochondrial DNA or mtDNA). A significant property of DNA is that it has the ability to

replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a

template for duplicating the sequence of bases. This is critical when cells divide so that each new

cell needs to have an exact copy of the DNA present in the old cell. [1]

It is also a target for chemotherapy. The binding of peptides, small organic and inorganic

molecules to DNA can interfere with the numerous processes which include: transcription and

replication in which DNA participates. Such interferences can retard or prevent cell growth.

There are a few chemical/structural differences between human DNA and DNA from other cells

(e.g., cancer) and specific drug targeting or specificity can be difficult to achieve. Unlike the

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drugs that act on enzymes or protein receptors that operate via specific mechanisms or essential

groups, there are no principal mechanisms by which DNA-based drug can act.

For example, the principal feature that makes cancer cells different from normal cells is their

ability to undergo uncontrolled cell division. This requires constant mitosis and the need for a

steady supply of DNA and DNA precursors. Cancer chemotherapies or cytotoxic substances,

have therefore targeted the shutdown of DNA knowing full well that "normal" DNA will also be

shut down.

STRUCTURE

Primary Structure

The information in DNA is stored as a code made up of four chemical bases viz. Purines:

adenine (A), guanine (G), and Pyrimidines: cytosine (C), and thymine (T). Human DNA consists

of about 3 bn bases, and more than 99 percent of these bases are same in all people. The

sequence of these bases determines the information available for building and maintaining an

organism, similar to how letters of the alphabet appear in a certain order to form words and

sentences.

DNA bases pair up with each other, A pairs up with T and C with G, to form units called base

pairs often called Watson-Crick base pairs. Also each base is attached to a sugar molecule and a

phosphate molecule. All together, a base, sugar, and phosphate are called a nucleotide.

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Nucleotides are arranged in two long strands that form a spiral structure called a double helix.

The structure of the double helix is similar to a ladder, with the base pairs forming the ladder’s

rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder.

The purine and pyrimidine bases are linked together via a 5' phosphate group at the N-9 position

through a deoxyribose sugar at 3’ OH. The carbon chain of the sugar group is numbered starting

with the anomeric center (1) until it reaches the exocyclic methylene (5). Thus, the phosphate

groups are connected to the 2-deoxyribose ring at the 3' and 5' positions.[2]

Secondary Structure:

Watson and Crick built the famous model of DNA which depicts two DNA strands arranged

together in a double helix with a constant diameter. The structure of DNA of all species

comprises of two helical chains each coiled round the same axis, and each with a pitch of

34 ångströms (3.4 nanometres) and a radius of 10 ångströms (1.0 nanometres).[3]

DNA structure follows the basic Chargaff’s rule:

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a) The concentration of adenine equals to that of thymine. 

b) The concentration of guanine equals to that of cytosine. [4]

Chargaff's findings clearly signify that some type of heterocyclic amine base pairing exists in the

DNA structure.

Most DNA double helices are right-handed; i.e., if you hold your right hand out, with your

thumb pointed up and your fingers curled around your thumb, your thumb would be representing

the axis of the helix and your fingers would be representing the sugar-phosphate backbone. Only

one type of DNA i.e. Z-DNA is left-handed.

The DNA double helix is anti-parallel, which implies that the 5' end of one strand is paired with

the 3' end of its complementary strand (and vice versa). Nucleotides are linked to each other by

their respective phosphate groups, which bind the 3' end of one sugar to the 5' end of the next.

Not only are the DNA base pairs connected via hydrogen bonding, but the outer edges of the

nitrogen-containing bases are exposed and available for potential hydrogen bonding as well.

These hydrogen bonds provide easy access to the DNA for other molecules, including the

proteins that play vital roles in the replication and expression of DNA. [5]

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Proteins recognize H-bond donnors, H-bond acceptors, methyl groups (hydrophobic), the later

being exclusively in the major groove; there are 4 possible patterns of recognition with the major

groove, and only 2 with the minor groove.

Some proteins bind to DNA in its major groove, some other in the minor groove, and some need

to bind to both of them.

Major groove: It is filled with the nitrogen and oxygen atoms of base pairs with project inward

from the sugar phosphate backbones toward the center of the DNA.

Minor groove: It is filled with the nitrogen and oxygen of base pairs that project outward from

the sugarphosphate backbones toward the outer edge of the DNA.

Tertiary and Quaternary Structure:

DNA, inside the cell is always subjected to bending, folding, over winding and under

winding.  Such changes make stable DNA unstable or vice versa, because of the energy

constraints. Thermodynamically complaint B- DNA contains 10.6 bp per turn, and such DNA

without any constraints or stress or torsion, when placed on a flat surface it lays flat as a circular

molecule or a linear molecule.  Such DNA, which is free from stress, is called Relaxed DNA.

When a relaxed DNA is subjected to bends or openings of DNA, over winding or unwinding, its

base pairs per turn changes, and the DNA is subjected to stress and strain.  In order to overcome

such distortion, which has rendered the DNA unstable, the DNA twist around itself, like a

circular rubber band undergoing twisting, such a twists on its own thread is called Super coiling;

it is also referred to as tertiary structure.

This over winding is thermodynamically incompatible, so in order to accommodate the excess

number of coils, the helical DNA twists on its own length in space in left handed direction, like a

rubber band twist, in left handed way, such a twist is called super coil; in this case the super

coiling is positive.

Negative super coils help in stabilizing certain DNA structures i.e. Z-DNA, cruciform DNA,

triplex DNA. 

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It also helps in unwinding of the DNA during replication as replication bubble or during

transcriptional initiation as transcriptional bubble.

Features of Importance to Medical Chemistry

The bases are stacked on "top" of each other in the double stranded macromolecule which

provides stabilization.

The nucleotide bases are hydrogen bonded to each other: A with T and C with G (figure

below). Chains are complementary.

Diameter of double helix is constant.

Polar sugar phosphate group lies on the outside (forms polar interactions with water) and

the somewhat lipophilic nucleic bases are inside

For strands pointing in the 5' to 3' direction, a complementary 3' to 5' strand exists, for

example,

5'-TGCATG-3'

3'-ACGTAC-5'

The 3’ and 5’ end are “different functional groups”

The nucleic acid bases differ in nucleophilicity and reactivity.

Phosphate groups are diesters to a primary and one secondary carbon

Right handed rotation between the adjacent base pairs (about 36º) produces a double

helix with 10 bases per turn.

The glycosidic bonds that connect the base pair to its sugar ring are not directly opposite

each other and therefore the two sugar-phosphate backbones of the double helix are

unequal along the helical axis which gives rise to the major and minor grooves.

If the double helix unravels, then a new chain can be constructed on each original chain

i.e. there are two templates for new double helix molecules.

The core of DNA is hydrophobic and the exterior faces the solvent (water), just like most

proteins.

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FORCES INVOLVED IN DNA-DRUG RECOGNITION

Some of the forces that are known to contribute to biomolecular recognition and also to DNA-

drug binding are direct electrostatic interactions, direct van der Waals/packing

interactions,complex hydration/dehydration contributions composed of hydrophobic component,

solvation electrostatics, solvation van der Waals, ion effects and entropy terms. DNA-drug

binding may be described in the following manner,

Consider DNA-drug binding in an aqueous environment. DNA is polyanionic in nature and the

drug molecule is also often charged. The associated counterions lie near the charged groups and

are also partially solvated. When binding occurs, it results in a displacement of solvent from the

binding site on both the DNA and drug. Also, since there would be partial compensation of

charges as the DNA and drug are oppositely charged, some counterions would be released into

the bulk solvent and are solvated fully. Also, the binding process would be associated with some

structural deformation/adaptation of the DNA as well as the drug molecule in order to

accommodate each other. All these events are associated with some energetic gains/losses, the

comprehensive estimation of which is a major challenge. Structural and conformational changes

in the DNA and drug on binding in solution are associated with enthalpic and entropic

contributions to the binding free energy, which can be theoretically estimated from ensembles of

structures generated via simulations.

The only drawback of this approach is the long time taken for the simulations. The other terms,

namely, electrostatics, van der Waals, hydrophobic component, rotational and translational

entropy can be estimated from single structures.[6]

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DRUGS

A drug is a Natural or synthetic substance which (when taken into a living body) affects its

functioning or structure, and is used in the diagnosis, mitigation, treatment, or prevention of a

disease or relief of discomfort.

According to FDA a drug is defined as:

A substance recognized by an official pharmacopoeia or formulary.

A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of

disease.

A substance (other than food) intended to affect the structure or any function of the body.

A substance intended for use as a component of a medicine but not a device or a component,

part or accessory of a device.

Biological products are included within this definition and are generally covered by the same

laws and regulations, but differences exist regarding their manufacturing processes (chemical

process versus biological process.)

Drug molecules that interact with DNA

A variety of compounds interact with DNA, ranging from complex natural product such as the

antibiotic triostin A to inorganic compounds like tris-platin. All of them bind to double stranded

DNA

There are four types of compounds that interact with DNA:

1. Intercalators

2. Groove binders

3. Alkylating agents

4. DNA cleaving agents

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INTERCALATORS

The phenomenon of intercalation involves the aromatic portion of a drug molecule positioning

itself between base-pairs. Intercalation increases the separation of adjacent base pairs and the

resultant helix distortion is compensated by adjustments in the sugar-phosphate backbone and an

unwinding of the duplex. The result of intercalation is that the DNA double helix becomes

geometrically distorted and the translation of genetic code may be unable to properly function.

Aromatic stacking interactions between the bases and the intercalating molecule are a major

stabilising feature of the complexes formed. Thus, intercalation represents a non-covalent

interaction between a drug and DNA in which the drug is held perpendicular to the axis.

Intercalators structure and mode of action

All these compounds contain a planar chromophore group of four fused six membered rings

variously substituted, and an amino sugar residue. They can have non-polar substituents, which

can be either cationic or neutral, that protrude into a groove region.

Generation of the intercalated complex causes extension of DNA, local unwinding of the base

pairs and other possible distortions in the backbone of DNA.

Specificity of intercalation usually favors G-C base pairs but groove-binding agents are far more

specific. Slight changes in the substituents, including stereochemical changes, significantly

change the biological activity. Daunomycin, for example, is most effective in the treatment of

leukemias, while adriamycin is more effective in the treatment of solid tumours. The different

complexes cryslallised have a 2:1 ratio of drug to DNA. [7][8]

Intercalation is favored energetically because the energy that holds the intercalated molecule

should be greater than normal base stacking (otherwise the drug would be let go). Also

intercalation does not disrupt normal DNA H bonding. However, it may destroy the regular

helical structure which leads to unwinding of the DNA at the binding site and significantly,

interferes with the DNA-binding enzymes (polymerases, topoisomerases, etc.)

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Intercalation is not a standalone phenomenon in drug action. it is normally the first step in

several stages that lead to DNA damage. The steps can include intercalation, interaction with

DNA base pairs, interaction with a protein, and non productive protein-DNA interaction.

Because they disrupt DNA structure, which is essential for cell proliferation, many intercalator

drugs are aimed at cancer.[9]

Categories of Intercalators:

There are several categories of intercalating agents viz. mono- and bis intercalators

Mono Intercalators:

ACRIDINES :

Acridines are tricyclic systems in which the nitrogen can be charged at a physiologic pH. They

are structurally related to anthracene with one of the central CH groups replaced by nitrogen.

Amino groups do not interrupt the H-bonding of nucleic bases but possibly furnish H-bonding to

sugar and phosphate backbone.

Acridine derivatives have a long history, beginning with antimicrobial activity that was reported

by Ehrlich and Benda in 1912, and exhibit several drug properties, such as anticancer, antibiotic,

antimalarial, antiprion, antinociceptive, antidimentia, anticiceptive, antileukemia, antipsychotic,

antidepressant, and telomerase inhibition. Their hydrophobicity allows them to diffuse into the

cell membrane and complex with (intercalate) DNA and RNA; giving them their drug properties

as well as causing fluorescence that can be used to study cellular processes like cell cycle

determination, stain nucleic acids, and flow cytometry. 

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Proflavine 9-Bromoacridine 1,3-Dihydroxy-9-acridinecarboxylic acid

PHENANTHRIDIUM:

Phenanthridines are angular tricyclics alkylated at nitrogen which furnish a permanent cation

charge. Amino groups do not interrupt H-bonding to nucleic bases. High trypanocidal activity in

the phenanthridine series is a property of quaternary salts containing a primary amino group in

the 7- and a phenyl group in the 9- position; the activity is much increased by the presence of a

second amino group, thus 2,7-diamino-9-phenyl-lO-methyl phenanthridinium bromide

(dimidium bromide) and the 10-ethyl analogue (ethidium bromide) are particularly effective A

crystal structure model has been obtained showing how ethidium binds DNA. Ethidium is often

used in the lab for staining DNA.[10][11]

Fig: Complex of ethidium bromide (an intercalating reagent) with DNA

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AROMATIC PEPTIDE HYBRIDS

These antibiotic structures bind to the double helix DNA between G-C pairs and the tricyclic part

of the molecule (oxazine) which intercalates DNA. The heterocycle is an iminoquinone.

Actinomycin D binds to a premelted DNA conformation present within the transcriptional

complex. This leads to immobilization the complex, hence interfering with the elongation of

growing RNA chains. [12]

ANTHRACYCLINE ANTIBIOTICS

Daunomycin led to one of the first crystal structures between intercalator and DNA. The sugar

group and A-ring lies in the minor groove of DNA and the ring with the methoxy group lies in

the major groove. The B and C rings are the core intercalative groups. [13]

When a daunomycin molecule is docked in DNA several things happen:

The intercalation site is opens 3.4 angstroms (creates a space) the minor groove is filled and water molecules are displaced by Cationic amino sugar and

ring A The Hydroxyl group on ring A forms Hydrogen bond with N3 and accepts and H bond

from amino group of the same G No unwinding of base pairs takes place at the intercalation site but unwinding takes place

at adjacent sites.

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CIS PLATIN

This is the only inorganic compound class which used in chemotherapy.It is sort of an

intercalator. Discovered in 1965, it binds strongly to DNA at oligoguanine sequences by

intrastrand binding and unwinds the duplex, reducing the length of the DNA molecule.

Interestingly, the transisomer is inactive. Cisplatin coordinates to DNA mainly through certain

nitrogen atoms of the DNA base pairs; these nitrogen atoms (specifically, the N7 atoms of

purines) are free to coordinate to cisplatin because they do not form hydrogen bonds with any

other DNA bases. Many types of cisplatin–DNA coordination complexes, or adducts, can be

formed. The most important of these appear to be the ones in which the two chlorine ligands of

cisplatin are replaced by purine nitrogen atoms on adjacent bases on the same strand of DNA;

these complexes are referred to 1,2-intrastrand adducts. The formation of these adducts causes

the purines to become destacked and the DNA helix to become kinked. Due to its

geometry, trans-DDP cannot form 1,2-intrastrand adducts with DNA. Since trans-DDP is

inactive in killing cancer cells, it is believed that the 1,2-intrastrand adducts formed between

cisplatin and DNA are important for the anticancer activity of cisplatin[14]

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Bis Intercalators:

These were invented with the thought that the dissociation constant for mono-intercalators could

be overcome by these multiple ring compounds. DNA bis-intercalators have two intercalating

groups in a single molecule and this enables these compounds to bind twice to a double stranded

DNA chain. the two intercalating groups of the molecule are joined together by a flexible linking

group about which they can rotate freely. Since the linking group is flexible, the free energy of

binding is more favourable.

The present invention relates to DNA bis- intercalators having two intercalating groups linked by

a rigid linker unit which has an extended c configuration. The requirement that the linker should

be rigid and have an extended configuration ensures that the two intercalating groups are kept

apart from each other at an essentially fixed distance and angle. The linker should be rigid so that

the intercalating groups are held apart and are extended such that they are kept apart to permit

one intercalating group to be free to bind to a DNA duplex when the other is already bound to a

different DNA duplex. The binding of both -intercalatorε into the same duplex is thus prohibited

unless the duplex folds back on itself to cross-link distant parts of. the same molecule. The bis-

intercalators with rigid linkers of the present invention, therefore, cross-link DNA duplexes to

form intermolecular links or cross-link distant parts of the same molecule. The binding of one

intercalating group leaves the other group pointing out from the binding site by virtue of the rigid

linker and so available for further binding to another DNA duplex. [14]

ACRIDINE SYNTHETICS

Acridine derivatives have been explored as DNA-binding anticancer agents. Some derivatives

show undesired pharmacokinetic properties and new derivatives need to be explored. In this

work, a series of novel acridine analogues were synthesized by modifying previously unexplored

linkers between the acridine and benzene groups and their antiproliferative activity and the

DNA-binding ability were evaluated. 

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QUINOXALINE ANTIBIOTICS

Quinoxaline antibiotic is a generic name given to a family of heterodetic cyclodepsipeptide

antibiotics which contain a quinoxaline moiety in the molecule. These colorless antibiotics are

derived from various species of Streptomycetes and are highly active against gram-positive

bacteria. They also exhibit a cytotoxic effect on cultured cells. The antibiotics were shown to

inhibit various experimental tumors and to protect mice from viral infection, although within a

narrow concentration range.

The molecular structure of triostin A, a cyclic octadepsipeptide antibiotic, has been solved

complexed to a DNA double helical fragment with the sequence CGTACG. The two planar

quinoxaline rings of triostin A bis intercalate on the minor groove of the DNA double helix

surrounding the CG base pairs at either end. The alanine residues form hydrogen bonds to the

guanines. Base stacking in the DNA is perturbed, and the major binding interaction involves a

large number of van der Waals contacts between the peptides and the nucleic acid. The adenine

residues in the center are in the syn conformation and are paired to thymine through Hoogsteen

base pairing.

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GROOVE BINDERS

The major and minor grooves of DNA differ in hydrogen-bonding, electrostatic potential,

hydration and sterics. Many proteins exhibit high specificity to the major groove region while

small molecules prefer the minor groove.[16]

Minor groove binding drugs are usually crescent shaped, which complements the shape of the

groove and facilitates binding by promoting van der Waals interactions. Minor-groove binding

molecules have aromatic rings connected by bonds with torsional freedom – molecules that can

twist into a shape that complements binding to the minor groove [with displacement of water].

Additionally, these drugs can form hydrogen bonds to bases, typically to O2 of thymine and N3

of adenine. Mostly, minor groove binding drugs bind to A/T rich sequences. This preference in

addition to the designed propensity for the electronegative pockets of AT sequences is probably

due to better van der Waals contacts between the ligand and groove walls in this region, since

A/T regions are narrower than G/C groove regions and also because of the steric hindrance in the

latter, presented by the C2 amino group of the guanine base. However, a few synthetic

polyamides like lexitropsins and imidazole-pyrrole polyamides have been designed which have

specificity for G-C and C-G regions in the grooves.[17]

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Some minor groove binders actually react with DNA. CC-1065 is an extremely potent cytotoxin

with sequence-selective binding in the minor groove of DNA followed by alkylation

(cyclopropyl group) at adenine residues.

Alkylation at adenine results in a breakof the glycosidic bond, and thus, a single-stranded break

in DNA on the 3’-side of the modified adenine. CC-1065 was too toxic so it was synthetically

modified to U-71184 – enhanced antitumor activity, low side effects.

NETROPSIN

Netropsin, has two DNA binding enthalpies in isothermal titration calorimetry (ITC) experiments

that indicate the compound simultaneously forms two thermodynamically different complexes at

a single AATT site. Two proposals for the origin of this unusual observation have been

developed: (i) two different bound species of netropsin at single binding sites and (ii) a netropsin

induced DNA hairpin to duplex transition. 

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ALKYLATING AGENTS

Alkylation represents an irreversible binding to DNA.

Biological substitution reactions regard the substrate (the alkylating agent) as minor and the

nucleophile as the "important" species. The biological approach takes into account that the

nucleophile is a macromolecule whose structure and function can be altered by even a minor

alteration.

In typical substitution reactions, the nucleophile can be an amine, sulfide, alcohol

The susbtrate R - X can be an alkyl halide or Michael acceptor.

By definition, alkylation means the transferof an alkyl group and the reaction must take place at

physiologic pH (approx. 7.4). Two reactions are shown above: neutral substrate and charged

nucleophile and neutral substrate and neutral nucleophile. There is an electronic difference in the

nature of the products.[19]

Common functional groups that serve as alkylating agents -

alkyl iodides, bromides, and other group leaving groups attached to primary alkanes:

methyl and ethyl iodide (CH3I, CH3CH2I), methyl triflate (Me-OSO2CF3)

Michael acceptors: acrylates (CH2=CH-CO2R; R = H, alkyl, aryl), alkynoates (RC≡C-

CO2R)

small rings: epoxides, aziridines, episulfides, cyclopropanes

The general biological nucleophilic groups modified by an alkylating agent are:

Page | 19

guanine N-7 > adenine N-3 > adenine N-1 > cytosine N-1 also some O-alkylation (enol

tautomer)

Thus, alkylation of guanine results in the formation of an N-7 "conjugate."

The consequences of alkylation at a nucleic base may be tolerated or deadly:

Mono-methylation at N7 guanine – does notchange base pairing, apparently seems

harmless.

Cross-linking of two N7-guanines – a cell killing event for either intra or interstrand.

Mono-alkylation of N3 adenine – the major toxic lesion resulting from monoalkylation.

Blocks the progress of DNA polymerases. Far more prevalent than mono-alkylation of

the N3 guanine.

O6-alkyl guanidines – locked in enol form and then does not base pair with C or T. This

alkylation does not block DNA polymerase and therefore, daughter strands are produced

with C or T opposite an O6-alkyl guanidine. A mismatch is now produced (G to A

transition).[20]

MUSTARDS

β-chloroethylamino or β-chloroethylmercapto groups that cyclize at physiologic pH to afford

aziridine and episulfide rings that are highly reactive (like epoxides). This reactive group is

present on lots of chemotherapeutics. The mechanism of cross-linking DNA by

Page | 20

mechlororethamine is shown in Fig. In this case, two betachloroethylamino groups are activated

stepwise to react with two nucleic bases.

Page | 21

DNA CLEAVING AGENTS

Some DNA reactive molecules can initially intercalate but under certain conditions generate

radical (C•) species that react with sugars residues of DNA causing DNA strand scission and a

breakdown of the ribose group

BLEOMYCIN

Bleomycin injection is used alone or in combination with other medications to treat head and

neck cancer (including cancer of the mouth, lip, cheek, tongue, palate, throat, tonsils, and

sinuses) and cancer of the penis, testicles, cervix, and vulva (the outer part of the vagina).

Bleomycin is also used to treat Hodgkin's lymphoma (Hodgkin's disease) and non-Hodgkin's

lymphoma (cancer that begins in the cells of the immune system) in combination with other

medications.

Page | 22

It is also used to treat pleural effusions (a condition when fluid collects in the lungs) that are

caused by cancerous tumors. Bleomycin is a type of antibiotic that is only used in cancer

chemotherapy. It slows or stops the growth of cancer cells in your body.

In this multistep process, initially an “activated” Fe(II)·bleomycin·O2complex is formed that is

kinetically competent to cleave DNA. The binding of dioxygen to Fe(II)·bleomycin proceeds

most rapidly in the presence of DNA, which stabilizes the complex.. Fe(II) combines with

apobleomycin, producing an EPR-silent, high-spin Fe(II)·bleomycin complex. With dioxygen,

this is rapidly converted to a ternary Fe(II)·bleomycin·O2species, which can be trapped with

isocyanide, CO, or NO or can be activated by a 1e- reduction. The e- can be supplied by a second

Fe(II)·bleomycin·O2 molecule, by H2O2, by microsomal enzymes and nicotinamide-adenine

dinucleotide phosphate (reduced form) (NADPH) organic reductant, or by nuclei and

nicotinamide-adenine dinucleotide (reduced form) (NADH).Mossbauer studies suggest that the

activated bleomycin has a half-life of a few minutes at 0°C, so it is likely to be reasonably long

lived even at 37°C. In the absence of DNA, the activated species will self-destruct.[21]

Page | 23

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3. Watson J.D. and Crick F.H.C. (1953). "A Structure for Deoxyribose Nucleic Acid" (PDF). Nature 171 (4356): 737–738. 

4. Chargaff, E. (1950) .Chemical specificity of nucleic acids and mechanism of their enzymatic degradation. Experientia 6, 201–209 ---. Preface to a grammar of biology. Science 171, 637–642 (1971)

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6. Saher Afshan Shaikh and B. Jayaram DNA Drug Interaction, Department of Chemistry and Supercomputing Facility for Bioinformatics and Computational Biology, Indian Institute of Technology

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9. Mukherjee, A; Lavery,R; Bagchi, B; and James, T.(2008),On the Molecular Mechanism of Drug Intercalation into DNA: A Simulation Study of the Intercalation Pathway, Free Energy, and DNA Structural Changes. J. Am. Chem. Soc., 2008, 130 (30), pp 9747–9755 American Chemical Society

10. NEWTON, B. A. (1957). The Mode of Action of Phenanthridines: The Effect of Ethidiurn Bromide on Cell Division and Nucleic Acid Synthesis. J. gen. Microbiol. 17, 718-730

11. Brit. J. (1950) THE CHEMOTHERAPEUTIC ACTION OF PHENANTHRIDINE COMPOUNDS PART I TRYPANOSOMA CONGOLENSE AND TRYPANOSOMA RHODESIENSE. Phannacol., 5, 261

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