**3. Anticancer drug-DNA interaction**

*Biophysical Chemistry - Advance Applications*

**2. Structural features of DNA**

molecules and proteins [4, 5].

pattern due to Watson-Crick hydrogen bonding [2, 3].

ladder.

resembles a ladder, with the phosphate and sugar molecules forming the ladder's vertical sidepieces. On the other hand, the base pairs form the rungs of the

Many anticancer drugs in clinical use interact with DNA through intercalation, which can be defined as the process by which compounds containing planar aromatic or heteroaromatic ring systems are inserted between adjacent base pairs perpendicularly to the axis of the helix and without disturbing the overall stacking

DNA consists of two complementary anti-parallel sugar phosphate poly-deoxyribonucleotide strands that are associated with specific hydrogen bonding between nucleotide bases. The two strands are held together primarily through Watson-Crick hydrogen bonds where A forms two hydrogen bonds with T and C forms three hydrogen bonds with G (**Figure 1**). The structure of these paired strands defines the helical grooves, within which the edges of the heterocyclic bases are exposed. The biologically relevant B-form of the DNA double helix is characterized by a shallowwide major groove and a deep-narrow minor groove. The chemical structure (feature) of the molecular surfaces in a given DNA sequence is well known in either groove. This forms the basis for molecular recognition of duplex DNA by small

*Watson-Crick pairing between purine and pyrimidine bases in complementary DNA strand.*

**76**

**Figure 1.**

DNA as carrier of genetic information is a major target for anticancer drug interaction because of the ability to interfere with transcription and DNA replication, a major step in cell growth and division. There are three principally different ways of anticancer drug binding. First is through control of transcription factors and polymerases. Here, the anticancer drugs interact with the proteins that bind directly to DNA. Second is through RNA binding to DNA double helices to form nucleic acid triple helical structures or RNA hybridization to exposed DNA single strand regions that will be forming DNA-RNA hybrids and it may interfere with transcriptional activity. Third is through small aromatic ligand molecules that bind to DNA double helical structures through non-covalent interaction either by intercalating binder or by minor groove binders (**Figure 2**) [6, 7]. Therefore, intercalation can be defined as the process by which compounds containing planar aromatic or heteroaromatic ring systems are inserted between adjacent base pairs perpendicularly to the axis of the helix and without disturbing the overall stacking pattern due to Watson-Crick hydrogen bonding [8]. In addition, intercalation binding 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. While groove binding, unlike intercalation, does not induce large conformational changes in DNA and may be considered similar to standard lock-and-key models for ligand-macromolecular binding. In addition, Groove binders are usually crescent-shaped molecules that bind to the minor groove of DNA [7].

In order to accommodate the binder (like intercalation binder), DNA must undergo a conformational change to create a cavity for the incoming chromophore. The double helix is therefore partially unwound, which leads to distortions of the sugar-phosphate backbone and changes in the twist angle between successive base pairs (**Figure 3**) [8]. Once the drug has been sandwiched between the DNA base

**Figure 2.** *Groove binding to the minor groove of DNA (left) and the intercalation into DNA (right).*

**Figure 3.** *Deformation of DNA by an intercalating agent.*

pairs, several non-covalent interactions such as Van der Waals interaction and hydrogen bonding optimizes the stability of the complex.

## **4. Types of drug-DNA interactions**

The study of interaction between drug molecules and DNA is very exciting and significant not only in understanding the mechanism of interaction, but also for the design of new drugs. However, the mechanism of interactions between them is still relatively little known. By understanding the mechanism of interaction between them, designing of new DNA-targeted drugs and the screening of these in vitro will be possible [9]. Many of the most valuable anticancer drugs currently used in therapy interact with DNA either by a covalent or non-covalent mechanism. Unfortunately, several of them show a considerable toxicity when the DNA molecular target is present in both normal and tumor cells [10]. The covalent type of binding of drug-DNA is irreversible and invariably causes the complete inhibition of DNA processes and subsequent cell death. A major advantage of covalent binders is the high binding strength. However, covalent bulky adducts can cause DNA backbone distortion, which affect both transcription and replication (disrupting protein complex recruitment). The covalent binders are also called alkylating agents due to adduct formation because they are used in cancer treatment to attach an alkyl group (CnH2n+1) to DNA [11]. **Table 1** lists the different types of drug-DNA interactions with suitable examples. In addition, some important examples of a cross-linking agent covalent and non-covalent binder were shown in **Figure 4** [5, 12].

**79**

*Anticancer Drugs' Deoxyribonucleic Acid (DNA) Interactions*

**No. Type of interaction Example**

*Listing the different types of drug-DNA interactions with suitable examples.*

1 Covalent bonding Nitrogen mustard, carboplatin and cyclophosphamide

2 Non-covalent bonding Ethidium bromide and quinacrine

Non-covalent DNA interacting agents (groove, intercalators, and external binders) are generally considered less cytotoxic than agents producing covalent DNA adducts and other DNA damage. The non-covalent binding type is reversible and is typically preferred over covalent adduct formation keeping the drug metabolism and toxic side effects in mind. In addition, non-covalent DNA interacting agents can changes DNA conformation, DNA torsional tension, interrupt protein-DNA

Hairpin minor grove binding molecules have been identified and synthesized that bind to G-C reach nucleotide sequences. Hairpin polyamides are linked systems that exploit a set of simple recognition rules for DNA base pairs through specific orientation of imidazole (Im) and pyrrole (Py) rings (**Figure 5**) [13]. They originated from the discovery of the three-ring Im-Py-Py molecule that bound to minor

The solid phase synthesis of polyamides of variable length has produced efficient ligands. The advantage of polyamide ligand design has been reached with finding structures able to recognize DNA sequences of specific genes. Moreover, a new strategy of rational drug design exploits the combination of polyamides with bis-intercalating structures. The new synthetic compound showed a resistant against multidrug resistance in which small aromatic compounds are efficiently

interaction, and potentially lead to DNA strand breaks [11].

*Chemical structure of some covalent and non-covalent binders of DNA.*

**5. Modeling of hairpin minor groove binders**

groove DNA as an antiparallel side by side dimer.

*DOI: http://dx.doi.org/10.5772/intechopen.85794*

**Table 1.**

**Figure 4.**

*Anticancer Drugs' Deoxyribonucleic Acid (DNA) Interactions DOI: http://dx.doi.org/10.5772/intechopen.85794*


#### **Table 1.**

*Biophysical Chemistry - Advance Applications*

pairs, several non-covalent interactions such as Van der Waals interaction and

agent covalent and non-covalent binder were shown in **Figure 4** [5, 12].

The study of interaction between drug molecules and DNA is very exciting and significant not only in understanding the mechanism of interaction, but also for the design of new drugs. However, the mechanism of interactions between them is still relatively little known. By understanding the mechanism of interaction between them, designing of new DNA-targeted drugs and the screening of these in vitro will be possible [9]. Many of the most valuable anticancer drugs currently used in therapy interact with DNA either by a covalent or non-covalent mechanism. Unfortunately, several of them show a considerable toxicity when the DNA molecular target is present in both normal and tumor cells [10]. The covalent type of binding of drug-DNA is irreversible and invariably causes the complete inhibition of DNA processes and subsequent cell death. A major advantage of covalent binders is the high binding strength. However, covalent bulky adducts can cause DNA backbone distortion, which affect both transcription and replication (disrupting protein complex recruitment). The covalent binders are also called alkylating agents due to adduct formation because they are used in cancer treatment to attach an alkyl group (CnH2n+1) to DNA [11]. **Table 1** lists the different types of drug-DNA interactions with suitable examples. In addition, some important examples of a cross-linking

hydrogen bonding optimizes the stability of the complex.

**4. Types of drug-DNA interactions**

*Deformation of DNA by an intercalating agent.*

**78**

**Figure 3.**

*Listing the different types of drug-DNA interactions with suitable examples.*

#### **Figure 4.**

*Chemical structure of some covalent and non-covalent binders of DNA.*

Non-covalent DNA interacting agents (groove, intercalators, and external binders) are generally considered less cytotoxic than agents producing covalent DNA adducts and other DNA damage. The non-covalent binding type is reversible and is typically preferred over covalent adduct formation keeping the drug metabolism and toxic side effects in mind. In addition, non-covalent DNA interacting agents can changes DNA conformation, DNA torsional tension, interrupt protein-DNA interaction, and potentially lead to DNA strand breaks [11].

### **5. Modeling of hairpin minor groove binders**

Hairpin minor grove binding molecules have been identified and synthesized that bind to G-C reach nucleotide sequences. Hairpin polyamides are linked systems that exploit a set of simple recognition rules for DNA base pairs through specific orientation of imidazole (Im) and pyrrole (Py) rings (**Figure 5**) [13]. They originated from the discovery of the three-ring Im-Py-Py molecule that bound to minor groove DNA as an antiparallel side by side dimer.

The solid phase synthesis of polyamides of variable length has produced efficient ligands. The advantage of polyamide ligand design has been reached with finding structures able to recognize DNA sequences of specific genes. Moreover, a new strategy of rational drug design exploits the combination of polyamides with bis-intercalating structures. The new synthetic compound showed a resistant against multidrug resistance in which small aromatic compounds are efficiently

**Figure 5.** *Structure of hairpin polyamide Im-Py-Py.*

expelled from the cell-by-cell membrane transport proteins that commonly referred to as ABC transporters or ATP binding cassette proteins [14].
