Drugs Acting on DNA: Intercalating Agents

• Drugs acting on DNA can be categorized by their mode of action: Intercalating agents, Topoisomerase poisons, Alkylating agents, Metallating agents, Chain cutters, and Chain terminators.

Intercalating Agents

• These agents contain planar or heteroaromatic features that allow them to slip between the base pairs of the DNA double helix.
• The rings of the drug are held in place through van der Waals interactions with the base pairs.
• Some can interact with the charged phosphate groups of the DNA backbone.
• Once inserted, the drug can prevent replication and/or transcription, leading to cell death.
• Proflavine is an example. It has a planar tricyclic system, but is dangerous for systemic use.
• Proflavine is used topically because it destroys the DNA preventing replication.

Dactinomycin

• This is an anti-cancer drug with two cyclic pentapeptides.
• It has a flat tricyclic heteroatom structure that provides extra binding to the sugar phosphate backbone by cyclic peptides.
• It intercalates between the minor groove of the DNA double helix and prefers interactions between guanine-cytosine.
• Dactinomycin prevents unwinding of DNA and blocks transcription by blocking DNA-dependent RNA polymerase.

Topoisomerase Poisons

• They are non-intercalating agents that stabilize the complex between DNA and topoisomerase enzymes.
• These prevent the rejoining of the DNA strand, and don't intercalate into the DNA helix.
• They are used as anti-cancer agents and cause chain cutting.
• Camptothecin is an example and was extracted from a Chinese bush in 1966.
• Camptothecin stabilizes the complex between DNA and topoisomerase I, leading to single-strand breaks that accumulate in the chain.
• This leads to irreversible double-strand breaks during transcription.

Alkylating Agents

• They contain highly electrophilic groups that form covalent bonds to nucleophilic groups in DNA.
• These agents can prevent replication and transcription and are useful as anticancer agents.
• They can cause interstrand and intrastrand crosslinking if two electrophilic groups are present.
• Alkylation of nucleic acid bases can result in miscoding.

Metallating Agents

• These were discovered when bacterial cell division was inhibited by a product of the electrolysis from platinum electrodes.
• They are neutral inactive molecules acting as a prodrug.
• Platinum is covalently linked to chloro substituents.
• Once in cell water, displacement of the chloro substituents creates a positively charged species that can act as a metalating agent.

Chain Cutters

• These cut the strands of DNA and prevent the enzyme DNA ligase from repairing the damage.
• They may act by creating radicals in the DNA structure.
• The radicals then react with oxygen to form peroxy species, which leads to DNA chain fragments.
• Calicheamicin is an example, it's an antitumor agent from bacteria.
• It binds to the major groove of DNA and generates a DNA diradical.
• The DNA diradical reacts with oxygen, resulting in chain cutting.

Chain Terminators

• These drugs act as "false substrates" and are incorporated into a growing DNA strand during replication.
• These drugs are "mistaken" for nucleotide triphosphates and must satisfy 3 conditions.
• They must be recognized by the DNA template.
• They must contain a triphosphate group to allow them to undergo the same enzyme-catalyzed addition to the chain as the normal building blocks.
• Their structure must make the addition of more nucleotides impossible.

Drugs that act on DNA can be categorized by their mode of action. Intercalating agents can prevent replication and transcription, leading to cell death. Proflavine and Dactinomycin are examples of intercalating agents.