Chemistry of Anti-Cancer Drugs

3 traditional approaches to treat cancer

• surgery

• radiotherapy

• chemotherapy

Why is combination therapy used?

• increased efficiency of action

• decreased toxicity and evasion of drug resistance

How do anticancer drugs work?

• disrupting function of DNA

• classed as cytotoxic

What are the main anti-cancer agents that directly interact with DNA to inhibit its various functions?

• alkylating and metalating agents

• intercalating agents

• topoisomerase poisons

• chain cutters

• chain terminators

What are antimetabolites?

• these inhibit enzymes involved in synthesis of DNA

  • dihydrofolate reductase inhibitors

  • thymidylate synthase inhibitors

  • ribonucleotide reductase inhibitors

  • adenosine deaminase inhibitors

  • DNA polymerase inhibitors

What is tubulin?

• a structural protein crucial in cell division

• anti-cancer drugs can act on structural proteins

What drug acts on tubulin?

• paclitaxel binds to tubulin and causes cell division cycle to be halted

• this drug has been used to treat cervical cancers

What are matrix metalloproteinase inhibitors?

• zinc dependant enzymes that degrade extracellular matrix and encourage angiogenesis, tumour, propagation and metastasis

What are alkylating agents?

• contain highly electrophilic groups that form covalent bonds to nucleophilic groups in DNA

• can be toxic side effects

• prevent replication and transcription

• cause interstrand and intrastand crosslinking if two electrophilic groups present

What are some examples of alkylating agents?

• nitrogen mustards

  • chlormethine

  • L-phenylalanine

  • uracil

  • estramustine

  • chlorambucil

  • ifosfamide

What is chlormethine?

• highly reactive nitrogen mustard

• reacts with water, blood, tissues

• too reactive to survive oral route and must be administered via IV

What are metalating agents?

• a chemical reaction that forms a bond to a metal

• Cis-platin is a metalating agent used to treat cancer

• commonly used to treat testicular and ovarian cancer

How is Cis-platina activated?

• activated in cells with low chloride ion concentration

• causes chloro substituents to be replaced with neural water ligands forming a positive charges species

What is the mechanism of action for metalating agents?

• cisplatin binds to DNA in regions rich in guanine units and causes intrastand crosslinks rather than interstrand crosslinks

• causes localised unwinding of DNA double helix and thus inhibits transcription

What are intercalating agents?

• contain planar aromatic or heteroaromatic ring systems

• these planar systems slip between layers of nucleic acid pairs and disrupt shape of helix

• intercalation prevents replication and transcription

What are some examples of an intercalating agents?

• proflavine

• dactinomycin

• doxorubicin

What are bleomycin?

• complex natural products have the advantage of not to cause bone marrow depression

• bithiazole ring system intercalates with DNA and N atoms chelate a ferrous ion

• interacts with oxygen and is oxidised to a ferric ion leading to generation of a superoxide or hydroxyl radicals

• these highly reactive species abstract H atoms from DNA - DNA strands being cut

• bleomycin appears to prevent enzyme DNA ligase from repairing damage caused

What are chain cutters?

• intercalating agents that cut strands of DNA and prevent enzyme DNA ligase from repairing the damage

• create radicals on DNA structure that then react with oxygen that leads to chain cutting

What is calicheamicin?

• a natural product which reacts with nucleophiles to produce a diradical species

• reaction with DNA ultimately leads to cutting of DNA chains

What is the action of topoisomerase II?

• relives the strain in DNA helix by temporarily cleaving DNA chain and crossing an intact strand through the broken strand

What are the example of topoisomerase poisons?

• etoposide

• teniposide

• stabilise covalent intermediate between DNA and topoisomerase II

What is topotecan?

• another anti-cancer drug

• treats advanced ovarian cancer

• semi-synthetic analogues of camptothecin

What does camptothecin do?

• target the complex between DNA and topoisomerase I

• leads to DNA cleavage and cell death if DNA synthesis is in progress

• these agents are toxic to cancer cell not synthesising new DNA

• due to alternative mechanism of action