DNA Targeting Drugs

Polynucleotides (DNA and RNA) are important but less interrogated targets in medicinal chemistry.
There are many compounds that interact with RNA, making it a key area for research.
The lecture focuses on drugs that interact with DNA, specifically:
- Intercalating agents
- Chain terminators
- Alkylating agents (case study)

DNA structure familiar, use Spartan to build and visualize DNA.
Exterior: Phosphate backbones (water soluble due to oxygen atoms and hydrogen bonding).
Internal region: Hydrophobic base pair stacking.
Chirality: Arises from the helicity of the DNA molecule.
10 base pairs per turn (36 degrees rotation between each base pair).
Distance between base pairs: $3.375$ angstroms, allowing for intercalators to slip in.

Proteins have structural variability due to 20 amino acids, making them good drug targets.
DNA, with only four building blocks, can still be a useful drug target because:
- Nuclear bases have different structures.
- Molecules can be selective for contiguous base pairs.
- Helicity, major and minor grooves, polar phosphate backbone, and hydrophobic interior provide structural elements.

Slide between base pairs (adenine, guanine, cytidine, thymidine).
Design analogs of native substrates/building blocks to slide between base pairs.
Non-covalent interactions (Van der Waals, pi-pi stacking) disrupt structural integrity.
Disruption of DNA structure affects copying templates, replication, and protein translation.
Intercalating drugs can have pendant groups with positively charged amine groups that interact with the phosphate backbone via electrostatic interactions (salt bridges).

Tricyclic fused aromatic ring system (planar).
Neutral amine group and charged group.
Slides between base pairs, disrupts DNA helicity, leading to repair mechanisms or apoptosis.
Crystal structure data shows proflavin disrupting the helicity of DNA.

Contain an intercalating motif and a pendant amine group.
Amine group (cationic at physiological pH) can swing around and interact with the phosphate DNA backbone.

Disrupt DNA synthesis by acting as false substrates.
Mimic nucleotide triphosphates but halt the addition of further building blocks.

Guanine triphosphate base pairs with cytosine.
Hydroxyl group on the preceding residue undergoes nucleophilic attack to liberate guanine.

Antiviral drug, chain terminator.
Contains an authentic guanine base but a modified (hydrolyzed) ribose unit.
Prodrug: inactive until phosphorylated by the virus in infected cells.
The triphosphate group is appended by the virus, making the drug active.
Recognition between guanine and cytidine occurs, but no hydroxyl group is available for nucleophilic attack.

Sulfur mustard (nerve gas in WWI and WWII) found to cause low white blood cell counts and defective bone marrow development.
Led to the idea of using controlled doses of toxic agents as anti-tumor agents.
Mustine was one of the first agents with clinical utility.

Chlorine is electronegative, making it a good leaving group.
Carbon-chlorine bond is polarized (delta negative Cl, delta positive C).
Nitrogen lone electron pair attacks the delta positive carbon, displacing chloride.
Forms an aziridinium ion (reactive due to the three-membered ring).
The aziridinium ion is attacked by a lone electron pair, forming a covalent bond with DNA.
The same chemistry repeats, cross-linking DNA.

Alkylating agent containing a metal ion (platinum).
Used in combination therapy to improve the survival rate of testicular cancer.
Accidental discovery by Rosenberg in 1965 during an experiment with E. Coli and electrolysis.

Platinum is in the $+2$ oxidation state.
Administered with amine and chloride ligands to reduce toxicity.
The compound is neutral overall, allowing it to cross cell membranes.
High chloride concentration outside the cell maintains stability.
Inside the cell, low chloride or high water promotes aquation (displacement of chloride by water).
Forms a cationic intermediate (higher propensity for forming to the negatively charged backbone).
Another aquation reaction displaces the other chloride ion.
Forms two covalent bonds between platinum and DNA (bisalkylation).
Radically changes the structure of DNA.

Atomic level data shows platinum covalently bonded to contiguous nucleotides, disrupting DNA structure.
This is an intrastrand alkylation, not an interstrand alkylation.
Intrastrand alkylation hits guanine, specifically the N7 atom.

A 1,2-deoxyguanine-phosphate-guanine accounts for 65% of the alkylation induced by cisplatin.
An Adenine guanine accounts for 25% of the material having done that experiment.

Discovered in 1989, these proteins have an L-shape and are high in alpha-helical content.
Recognize platinator DNA and are part of a ternary structure (platinum, DNA, protein)
Their role is uncertain: may inhibit DNA repair or cause additional binding.

Administered intravenously, plasma half-life is short (25-50 minutes).
High affinity to sulfur means it binds to sulfur-containing proteins and peptides (glutathione, metallothionein) in off-target mechanisms.

Neutral cisplatin outside the cell converts to cationic species inside the cell due to low chloride and high water concentrations.
Cationic species are attracted to the negatively charged phosphate backbone of DNA.
Preference towards N7 of guanine compromises DNA structure.
High mobility group proteins are involved in the platinator DNA mechanism.