Lecture 5: DNA Alkylating and Platinating Agents EXAM 1 CUTOFF

What is the desired drug target of DNA alkylating and platinating agents?

DNA

What do alkylating agents add to DNA?

C, H

What do platinating agents add to DNA?

Pt

DNA alkylating agents cause DNA ______ which causes failed DNA ______ and/or ______ which ultimately causes ______ ______

damage; replication; repair; cell death

DNA alkylating agents can chemically damage DNA regardless of the ______-______ ______

cell-cycle phase

The consequences of the DNA damage caused by alkylating agents becomes especially important when the cell tries to ______ ______ ______

replicate damaged DNA

In general, rapidly ______ cancer cell are more ______ to cell death from damaged DNA

proliferating; vulnerable

Chemically, DNA alkylating agents as anti-cancer drugs are highly reactive ______ ______

electrophilic compounds

E+ contain a full or partial ______ charge

positive

E+ contain a good ______ ______

leaving group

Chemically, DNA alkylating agents as anti-cancer drugs will react ______ with ______ functional groups

covalently; nucleophilic

Nucleophilic groups contain a ______ charged atom

negatively

Nucleophilic groups contain an atom with a ______ ______ of electrons

lone pair

What is the result of DNA alkylating agent combined with DNA nucleophile?

alkylated DNA which causes desired anticancer effect

What is the result of DNA alkylating agent combined with protein or enzyme nucleophile?

possible anticancer effect, but more likely long-lasting adverse effects

What is the result of DNA alkylating agent combined with water or glutathione?

inactive metabolites with no anticancer activity

What is the chemical problem with DNA alkylating agents as anticancer drugs?

there are a ton of different nucleophiles found within the human body

The single most important nucleophile for DNA alkylating agents is what?

N7 atom of guanine within DNA of cancer cell

How likely is our DNA alkylating agent going to selectively react with the "desired" nucleophile and nothing else???

very unlikely

DNA alkylating agents can have some of the worst, long-lasting ______ ______

adverse effects

Why do DNA alkylating agents have some of the worst, long lasting adverse side effects?

formation of covalent, irreversible drug-off target complexes and lack of drug target selectivity and cell type selectivity

What structural feature makes nitrogen mustards capable of cross-linking DNA?

two 2-chloroethyl groups

What do the 2-chloroethyl groups in nitrogen mustards do?

cause bifunctional alkylation which causes inter or intra-strand DNA cross-linking

Why does DNA cross-linking kill the cancer cell?

DNA cannot unwind to function as a template for DNA replication or DNA transcription to mRNA

What happens to cancer cells when the DNA cannot unwind for DNA replication or DNA transcription to mRNA?

cancer cell apoptosis

It is important to note that ALL DNA alkylating agents are potentially ______ and ______

mutagenic; carcinogenic

How can DNA alkylating agents be carcinogenic?

secondary malignancies

What could DNA mutations resulting from the alkylation of DNA by a DNA alkylating agent lead to?

cell apoptosis, irreversible state of cell dormancy, conversion of a normal healthy cell into a cancer cell

How is cell apoptosis from DNA alkylating agents both good and bad?

good for a cancer cell but bad for a normal healthy cell

______ ______ is an irreversible state of cell dormancy

cell senescence

Why is cell senescence good?

allows the immune system to catch up which is good for a cancer cell

Cancer is a disease of our ______

genes

We cannot forget the importance of ______ ______ ______

DNA repair enzymes

What is the "major pathway" of DNA alkylating agents with normal healthy cell DNA?

normal healthy cell has time to detect and repair the damaged DNA so the normal healthy cell lives and continues to grow and divide

What is the "minor pathway" of DNA alkylating agents with normal healthy cell DNA?

undesired apoptosis of normal healthy cells that cause clinically observed undesired side effects

What is the "major pathway" of DNA alkylating agents with cancer cell DNA?

desired apoptosis of cancer cell which causes clinically observed desired anti-cancer effects

What is the "minor pathway" of DNA alkylating agents with cancer cell DNA?

DNA repair enzymes repair the cancer DNA and the cancer cell lives and continues to grow and divide

How can nitrogen mustards be rationally designed as DNA alkylating agents to improve their clinical properties?

yes via the R group

What is the prototype nitrogen mustard?

mechlorethamine

What was mechlorethamine initially used for?

lymphoma

What are the three main problems of meclorethamine?

lack of selectivity, high chemical reactivity, super short half-life

Mechlorethamine lacks selectivity and reactions with many ______

nucleophiles

Mechlorethamine is extremely ______ and is unstable in ______ ______

toxic; aqueous solution

Mechlorethamine is difficult to control clinically, so it is only used ______

IV

What is the modern role of melphalan?

myeloma

Melphalan is a nitrogen mustard linked to ______

L-phenylalanine

Why is melphalan linked to L-phenylalanine?

concerning aromatic amino acids, cancer cells in multiple myeloma have upregulated amino acid transporters which provides improved uptake in cells in particular cancer cells

Cancer cells have ______ amino acid transporters which provides improved ______ into cells in particular ______ ______, which is why melphalan is linked to ______

upregulated; uptake; cancer cells; L-phenylalanine

Melphalan displays improved ______ and has a ______ half-life

stability; longer

Melphalan can be used ______

orally

What is the modern role of bendamustine?

lymphoid malignancies

Bendamustine is a nitrogen mustard linked to a ______ ______ which looks like a ______

benzimidazole ring; purine

What can bendamustine act as?

DNA alkylating agent and purine anti-metabolite

Bendamustine forms DNA ______ as a nitrogen mustard

crosslinks

Bendamustine shows less drug ______

resistance

Bendamustine also has a more favorable ______ profile because it is more selective for ______ ______

toxicity; cancer cells

How is mechlorethamine activated?

directly reactive

What are the clinical consequences for mechlorethamine?

nonspecific alkylation of numerous biological macromolecules which causes severe toxicity

How is cyclophosphamide activated?

a prodrug that undergoes hepatic oxidation through CYP activation

What is the notorious drug metabolite from cyclophosphamide?

acrolein

What are the clinical consequences of cyclophosphamide?

hemorrhagic cystitis

How is ifosfamide activated?

a prodrug that undergoes hepatic oxidation through CYP activation

What are the notorious toxic metabolites of ifosfamide?

acrolein and chloracetaldehyde

What are the clinical consequences of ifosfamide?

hemorrhagic cystitis and encephalopathy