1. Cyclophosphamide is a chemotherapy medication used to treat various types of cancers (i.e. lymphoma, leukemia, and breast cancer). It belongs to a group of cytotoxic alkylating agents known as Nitrogen mustards. The activity of these drugs is attributed to the chloroethylamine groups. NH Cl R R Cyclophosphamide chloroethylamine In this exercise, you will explore the mechanism responsible for the cytotoxic activity of Nitrogen mustards and how it is possible to tune their activity (therefore their toxicity) by modifying their chemical structure. 1.5 Draw the curved arrows to complete the reaction mechanism of the following reaction. Start with the intramolecular reaction of chloroethylamine and then react the cyclic product with the primary amine. R. R Cl + R'-NH2 1.6 The chloroethylamine has two methylene groups [(CH2)2] between the nitrogen and the halide leaving group. Predict how the reactivity of the molecule will be affected by inserting a third methylene group [(CH2)3]. Explain why. R R. 'N' R N R 1.7 Now that you have figured out the reaction mechanism, let's explore the action mechanism of the following drug. Notice that this molecule is composed of two chloroethylamine groups and therefore can react with two different nucleophiles. Complete the following reaction mechanism. R'-NH2 R-N + R"-NH2 The above reaction is responsible for the activity of the drug. Because of its ability to react with two nucleophiles, the drug can create a bridge between two biologically active molecules and disrupt their activity. This process is known as 'cross-linking'. For example, it can react with two DNA strands and prevent their separation during replication. This will cause cytotoxicity and cell death. 1.8 Draw a scheme/cartoon to represent the general idea of chemical cross-linking. 1.9 The reactivity of nitrogen mustards can be tuned by changing the chemical structure. Compare the reactivity of the two molecules below. Which nitrogen is more nucleophilic? Why? Draw a resonance structure to support your reasoning.
1. Cyclophosphamide is a chemotherapy medication used to treat various types of cancers (i.e. lymphoma, leukemia, and breast cancer). It belongs to a group of cytotoxic alkylating agents known as Nitrogen mustards. The activity of these drugs is attributed to the chloroethylamine groups. NH Cl R R Cyclophosphamide chloroethylamine In this exercise, you will explore the mechanism responsible for the cytotoxic activity of Nitrogen mustards and how it is possible to tune their activity (therefore their toxicity) by modifying their chemical structure. 1.5 Draw the curved arrows to complete the reaction mechanism of the following reaction. Start with the intramolecular reaction of chloroethylamine and then react the cyclic product with the primary amine. R. R Cl + R'-NH2 1.6 The chloroethylamine has two methylene groups [(CH2)2] between the nitrogen and the halide leaving group. Predict how the reactivity of the molecule will be affected by inserting a third methylene group [(CH2)3]. Explain why. R R. 'N' R N R 1.7 Now that you have figured out the reaction mechanism, let's explore the action mechanism of the following drug. Notice that this molecule is composed of two chloroethylamine groups and therefore can react with two different nucleophiles. Complete the following reaction mechanism. R'-NH2 R-N + R"-NH2 The above reaction is responsible for the activity of the drug. Because of its ability to react with two nucleophiles, the drug can create a bridge between two biologically active molecules and disrupt their activity. This process is known as 'cross-linking'. For example, it can react with two DNA strands and prevent their separation during replication. This will cause cytotoxicity and cell death. 1.8 Draw a scheme/cartoon to represent the general idea of chemical cross-linking. 1.9 The reactivity of nitrogen mustards can be tuned by changing the chemical structure. Compare the reactivity of the two molecules below. Which nitrogen is more nucleophilic? Why? Draw a resonance structure to support your reasoning.
Chapter19: Aldehydes And Ketones: Nucleophilic Addition Reactions
Section19.SE: Something Extra
Problem 29VC
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Transcribed Image Text:1. Cyclophosphamide is a chemotherapy medication used to treat various types of
cancers (i.e. lymphoma, leukemia, and breast cancer). It belongs to a group of
cytotoxic alkylating agents known as Nitrogen mustards. The activity of these drugs is
attributed to the chloroethylamine groups.
NH
Cl
R
R
Cyclophosphamide
chloroethylamine
In this exercise, you will explore the mechanism responsible for the cytotoxic activity of
Nitrogen mustards and how it is possible to tune their activity (therefore their toxicity) by
modifying their chemical structure.
![1.5 Draw the curved arrows to complete the reaction mechanism of the following
reaction. Start with the intramolecular reaction of chloroethylamine and then react the
cyclic product with the primary amine.
R.
R
Cl
+ R'-NH2
1.6 The chloroethylamine has two methylene groups [(CH2)2] between the nitrogen and
the halide leaving group. Predict how the reactivity of the molecule will be affected by
inserting a third methylene group [(CH2)3]. Explain why.
R
R.
'N'
R
N
R
1.7 Now that you have figured out the reaction mechanism, let's explore the action
mechanism of the following drug. Notice that this molecule is composed of two
chloroethylamine groups and therefore can react with two different nucleophiles.
Complete the following reaction mechanism.
R'-NH2
R-N
+
R"-NH2
The above reaction is responsible for the activity of the drug. Because of its ability to
react with two nucleophiles, the drug can create a bridge between two biologically active
molecules and disrupt their activity. This process is known as 'cross-linking'. For
example, it can react with two DNA strands and prevent their separation during
replication. This will cause cytotoxicity and cell death.
1.8 Draw a scheme/cartoon to represent the general idea of chemical cross-linking.
1.9 The reactivity of nitrogen mustards can be tuned by changing the chemical
structure. Compare the reactivity of the two molecules below. Which nitrogen is more
nucleophilic? Why? Draw a resonance structure to support your reasoning.](/v2/_next/image?url=https%3A%2F%2Fcontent.bartleby.com%2Fqna-images%2Fquestion%2F0fcb0af8-b750-4635-b3ee-2f0c31e9ebdb%2F9450d840-ebc0-4b61-84b1-aa5aa1f3c83c%2Fxrku4bi_processed.jpeg&w=3840&q=75)
Transcribed Image Text:1.5 Draw the curved arrows to complete the reaction mechanism of the following
reaction. Start with the intramolecular reaction of chloroethylamine and then react the
cyclic product with the primary amine.
R.
R
Cl
+ R'-NH2
1.6 The chloroethylamine has two methylene groups [(CH2)2] between the nitrogen and
the halide leaving group. Predict how the reactivity of the molecule will be affected by
inserting a third methylene group [(CH2)3]. Explain why.
R
R.
'N'
R
N
R
1.7 Now that you have figured out the reaction mechanism, let's explore the action
mechanism of the following drug. Notice that this molecule is composed of two
chloroethylamine groups and therefore can react with two different nucleophiles.
Complete the following reaction mechanism.
R'-NH2
R-N
+
R"-NH2
The above reaction is responsible for the activity of the drug. Because of its ability to
react with two nucleophiles, the drug can create a bridge between two biologically active
molecules and disrupt their activity. This process is known as 'cross-linking'. For
example, it can react with two DNA strands and prevent their separation during
replication. This will cause cytotoxicity and cell death.
1.8 Draw a scheme/cartoon to represent the general idea of chemical cross-linking.
1.9 The reactivity of nitrogen mustards can be tuned by changing the chemical
structure. Compare the reactivity of the two molecules below. Which nitrogen is more
nucleophilic? Why? Draw a resonance structure to support your reasoning.
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