Many research articles have been published regarding the anti tumor properties of 9-aminoacridine based drugs, but to understand their effectiveness, one must look at the functions of these drugs on a molecular level and how they interact with DNA on a cellular level.
Apoptosis occurs when cells are infected or reach the end of their life cycle. In a cancer cell, apoptosis does not function properly because the cancer cell overrides the cells function to kill itself, so it can continue spreading. In a study done by Tan et. al. it was found that cancer cells can go through apoptosis if the DNA cannot replicate. This means that making out drug a catalytic inhibitor of DNA topoisomerase means that the cycle of cell replication is broken down and cancer cannot continue to metabolize and instead will kill itself (9).
DNA topoisomerase is an enzyme that is crucial in mitosis and meiosis or cell replication. DNA topoisomerase monitors topological changes in DNA allowing for replication, transcription, and decantation. It works by unwinding the DNA before the helicase unzips it. If the helicase keeps unzipping the DNA and the topoisomerase is inhibited, the DNA will not be able replicate making cell replication not possible and therefore induces apoptosis (10). DNA topoisomerase is needed to replicate and grow, making DNA topoisomerase affecting drugs very effective in the battle against cancer. Drugs affecting DNA topoisomerase can be very effective treatments for cancer (6).
According to Galvez-peralta et al, chemotherapy drugs affect the cells in two ways, they can either be a DNA topoisomerase poison or a catalytic inhibitor of DNA topoisomerase. Topoisomerase poison is when the drug prevents DNA replication after the DNA strands separate from each other. DNA poisons occur when the “cleavable complex” is stabilized and leads to covalent links between the enzyme and DNA, therefore leading to irreversible breaks and damage along the DNA. On the other hand, catalytic inhibitors of DNA topoisomerase can prevent any other step in the seven step catalytic cycle giving catalytic inhibitors of DNA topoisomerase a longer window to function (7).
In research done by Galvez, mice are used to test the effects of the 9-aminoacridine derivative on cancer. From the research, it can be concluded that 9-aminoacridine can break down the cancerous cell and induce cell death, although it is a catalytic inhibitor of DNA topoisomerase. Although this experiment was performed on mice, most of the results can be used with human DNA as well because of the vast similarities between our DNA compositions, making O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine, a catalytic inhibitor of DNA topoisomerase in our DNA as well (7).
In another article, Goodell (9) indicates that the 9-aminoacridine derived drugs are DNA catalytic inhibitors. By examining the other amino acridine derivatives and their behavior there is strong evidence to suggest that, O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine is a DNA catalytic inhibitor as well and will cause cancer cells to go into apoptosis.
Many currently available chemotherapy drugs are DNA catalytic inhibitors of topoisomerase in the cell but have no way of targeting the cancer cells specifically. Instead, the drug can affect many other cells which are beneficial to the body and lead to many side effects. 9-aminoacridine derived drugs are effective in killing the cancer cells but they are susceptible to hydrolysis and have to be taken in higher doses. To minimize this effect, O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine, would be less prone to hydrolysis making it more effective in smaller doses for a longer period of time (4).
Apoptosis occurs when cells are infected or reach the end of their life cycle. In a cancer cell, apoptosis does not function properly because the cancer cell overrides the cells function to kill itself, so it can continue spreading. In a study done by Tan et. al. it was found that cancer cells can go through apoptosis if the DNA cannot replicate. This means that making out drug a catalytic inhibitor of DNA topoisomerase means that the cycle of cell replication is broken down and cancer cannot continue to metabolize and instead will kill itself (9).
DNA topoisomerase is an enzyme that is crucial in mitosis and meiosis or cell replication. DNA topoisomerase monitors topological changes in DNA allowing for replication, transcription, and decantation. It works by unwinding the DNA before the helicase unzips it. If the helicase keeps unzipping the DNA and the topoisomerase is inhibited, the DNA will not be able replicate making cell replication not possible and therefore induces apoptosis (10). DNA topoisomerase is needed to replicate and grow, making DNA topoisomerase affecting drugs very effective in the battle against cancer. Drugs affecting DNA topoisomerase can be very effective treatments for cancer (6).
According to Galvez-peralta et al, chemotherapy drugs affect the cells in two ways, they can either be a DNA topoisomerase poison or a catalytic inhibitor of DNA topoisomerase. Topoisomerase poison is when the drug prevents DNA replication after the DNA strands separate from each other. DNA poisons occur when the “cleavable complex” is stabilized and leads to covalent links between the enzyme and DNA, therefore leading to irreversible breaks and damage along the DNA. On the other hand, catalytic inhibitors of DNA topoisomerase can prevent any other step in the seven step catalytic cycle giving catalytic inhibitors of DNA topoisomerase a longer window to function (7).
In research done by Galvez, mice are used to test the effects of the 9-aminoacridine derivative on cancer. From the research, it can be concluded that 9-aminoacridine can break down the cancerous cell and induce cell death, although it is a catalytic inhibitor of DNA topoisomerase. Although this experiment was performed on mice, most of the results can be used with human DNA as well because of the vast similarities between our DNA compositions, making O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine, a catalytic inhibitor of DNA topoisomerase in our DNA as well (7).
In another article, Goodell (9) indicates that the 9-aminoacridine derived drugs are DNA catalytic inhibitors. By examining the other amino acridine derivatives and their behavior there is strong evidence to suggest that, O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine is a DNA catalytic inhibitor as well and will cause cancer cells to go into apoptosis.
Many currently available chemotherapy drugs are DNA catalytic inhibitors of topoisomerase in the cell but have no way of targeting the cancer cells specifically. Instead, the drug can affect many other cells which are beneficial to the body and lead to many side effects. 9-aminoacridine derived drugs are effective in killing the cancer cells but they are susceptible to hydrolysis and have to be taken in higher doses. To minimize this effect, O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine, would be less prone to hydrolysis making it more effective in smaller doses for a longer period of time (4).
Figure 1. Step 1 in O-phenyl-N-(9’-acridinyl)-hydroxylamine
Figure 2. Step 2, Synthesis of O-phenyl-N-(9’-acridinyl)-hydroxylamine
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Research on the synthesis for another 9-aminoacridine derivative called O-phenyl-N-(9’-acridinyl)-hydroxylamine has already been synthesized by DeSelm (4). According to Ghosh (8) the synthesis of both is very similar with O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine, the only difference is an extra methyl group compared to O-phenyl-N-(9’-acridinyl)-hydroxylamine. In the first step, N-aryloxyimides and aryloxamines are synthesized. In the first step, Gosh et. al.’s research points out that p-iodotoluene and toluene can be used to make a Diaryliodonium salt. The process in which to combine the reactants is similar to the way that DeSelm combined his first two reactants to get Diaryliodonium salt as well.
The second step is also very similar to the second step outlined by DeSelm in his research. The second step consists of reacting the Diaryliodonium Salt from the first step and combining it with N-hydroxyphthalimide to get N-phenyloxyphthalimide. This research differs from DeSelm’s research because there is an extra methyl group attached to the compound which has properties to be synthesized more efficiently. Outlined below, in figure 2, is DeSelm’s second step which he outlined for the second step in the synthesis of O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine. |
The third step in synthesizing O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine is the hydrolysis of Hydrolysis of N-(4-methyl)-phenyloxyphthalimide. Which can be done by using the steps outlined by DeSelm once again. Once the N-(4-methyl)-phenyloxyphthalimine is created the next step begins, in which you do the hydrolysis of Hydrolysis of N-(4-methyl)-phenyloxyphthalimine to get O-(4-methyl)-phenyloxyphthalimide. Which can be done two different ways, all of them shown below. The final step is to synthesize O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine (4).For the fourth and final step of the synthesis of O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine was also
outlined by DeSelm and the process is shown below in figure 4.
outlined by DeSelm and the process is shown below in figure 4.
Figure 3. Step 3, Method 1 for the synthesis of O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine
Figure 4. Step 3, Method 2 for the synthesis of O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine
Figure 5. Step 4, Synthesis of O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine
Cancer is an epidemic that affects everyone differently, so there is a need for a large variety of cancer treatments that not only eradicate cancer but also are cost-effective for patients. Although some of the drugs in the steps can be purchased, the objective of this research is also to be cost effective and intern easy and cost effective to manufacture. O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine hopefully has the potential to be less susceptible to hydrolysis, an effective antitumor agent, and also cost effective.
Cancer is an epidemic that affects everyone differently, so there is a need for a large variety of cancer treatments that not only eradicate cancer but also are cost-effective for patients. Although some of the drugs in the steps can be purchased, the objective of this research is also to be cost effective and intern easy and cost effective to manufacture. O-(4-methyl)-phenyl-N-(9’acridnyl)-hydroxylamine hopefully has the potential to be less susceptible to hydrolysis, an effective antitumor agent, and also cost effective.