**8. Alzheimer**

In 1906, the German physician scientist Dr. Alois Alzheimer identified the microscopic changes in the brain of a patient with the memory loss. He was the first physician to identify the disease in a 50-year-old woman who suffered from psychosis and who died within 4 years. Using special dyes, he stained the brain tissues which carried abnormal protein deposit around her brain which controlled brain function. He identified two kinds of legions of amyloid patches which he mistakenly thought was fatty patches and now turned out to be proteins. He observed a patch of fatty deposit on the top of the brain cells called plaques and the legions inside the nerve cells called tangles. He accurately correlated the abnormal protein deposits around brain cells with the controlled of brain function [23–26].

Today, we know that the age is the single most risk factor for developing Alzheimer. By age 65 or older, the risk for developing Alzheimer is about 10%, and by age 85 or older, the risk factor is as high as 40 or 50%. As people grow old, they become senile. When he performed the autopsy of many senile persons, Dr. Alzheimer found the same plaques and tangles in many other samples. Early onset or late onset of Alzheimer resulted in the epidemic of Alzheimer. When comparing a normal brain with the Alzheimer brain, we find that the Alzheimer brain has shrunken and there is a concentration of plaques and tangles in neurons. In healthy brain cells, we see occasional plaques and tangles. It defines the disease; the plaque and tangles start building up as we grow old, and over years and decades, the symptoms begin to develop. Symptoms include memory loss and decrease in ability of learning and recall. Early onset affects cognition which encompasses memory

and other mental functions such as erosion of attention, thinking, reasoning, visual functions, spatial function, and dementia with memory loss and other cognitive functions resulting in mental impairment which affects to the degree interfering with the daily life.

Recent studies confirm that Alzheimer is an irreversible brain disorder which slowly destroys memory and thinking skills. The damage to the brain is not particularly associated to any specific gene, but the presence of the one form of the apolipoprotein E (APOE) is a suspect gene whose presence does increase a patient's risk for developing Alzheimer. The early onset of Alzheimer is associated with three single gene mutations: first, the presence of an amyloid precursor protein (APP) located on chromosome-21; the presence of presenilin 1 (PSEN1) on chromosome-14 and the presence of presenilin 2 (PSEN2) located on chromosome-1. All three chromosomes are very large and carry hundreds of genes. For example, chromosome-1 is the largest chromosome in the genome. It is made of 163 million nucleotide bases carrying 2610 genes. Chromosome-21 is made of 50 million nucleotide bases carrying 337 genes, while chromosome-14 is made of 109 million nucleotide bases carrying 1173 genes.

A recent 7 million Utah population study identified two additional genes RAB10 located on chromosome-2 (which is made of 155 million nucleotide bases and carry 1798 genes) and SAR1A gene located on chromosome-10 (which is made of 144 million nucleotide bases and carry 983 genes) associated with the formation of plaques and tangles. Mutations on these genes may be associated with the onset of Alzheimer.

Of all the genes on these chromosomes, only five single-gene mutations are associated with the early onset of the Alzheimer, it is the greatest challenge to design drugs to attack only the mutated genes. As I said above in the "Cancers" section, the good news is that the only mutated genes grow rapidly using glucose as a source of energy. Glucose is broken down to produce pyruvic acid. It is the acid which activates the aziridine and carbamate moieties producing powerful carbonium ion which attack N-7 guanine of DNA and shut off only the mutated genes. Other genes are not affected. Using C-14 radiolabeled aziridines, we can identify the mutated gene which form the aziridine/protein complex as described in the "Cancers" section.

### **9. Rationale for designing drugs to treat Alzheimer**

It is well known that using the TFT dye, which is 3,6-dimethyl-2-(4 dimethlaminophenyl)-benzothiazoline, could be used to stain the plaques and tangles of Alzheimer tissues. Using TFT dye as a carrier for the aziridine and carbamate moieties, we could design drugs to attack the mutated DNA to shut off genes which form plaques and tangles to prevent the progress of Alzheimer.

In the above "Cancers" section, I have described in detail how I had used quinone as a carrier for aziridine and carbamate ions in designing AZQ to attack the brain tumor DNA to shut off genes for treating brain cancer. Similarly, the analogs of benzothiazoline dyes could be used to carry aziridine and carbamate moieties to attack the plaque and tangle DNA and shut off genes responsible for causing Alzheimer.

### **10. What other cancers should we explore next?**

Could I use the same rational drug design and introduce a novel method for treating breast tumor?

**111**

*The Rational Drug Design to Treat Cancers DOI: http://dx.doi.org/10.5772/intechopen.93325*

to both male and female hormones.

the brain, I could focus on the breast and prostate cancers.

Although mutations on BRCA1 gene located on chromosome-17 (which is made of 92 million nucleotide bases carrying 1394 genes) have been identified years ago responsible for causing breast cancer, we wonder why it has been so difficult to design drugs on rational basis to treat breast cancer. By the time the breast cancer diagnosis is confirmed in a patient, the BRCA1 has accumulated more than 3000 mutations. Genotyping of the blood would also show the existence of many cells carrying mutated cells responsible for creating secondary deposits. It is also believed that by the time breast cancer is confirmed, metastatic cancer cells have already been spread from liver lung on its way to brain. Since all other organs including breast and liver could be removed and replaced by organ transplant except brain, I thought that protecting brain is utmost important to save life. Once AZQ is developed to protect

Recent, radiolabeled studies showed that male hormone testosterone has great affinity for female organs like breast, ovary, and fallopian tube cells. On the other hand, estrogen, the female hormone, has great affinity for male prostate gland. By attaching multiple aziridine rings and carbamate ions to both hormones, I could design novel drugs to attack the breast and the prostate cancer. Now, I found that I could go even further by attaching more than four aziridine and carbamate moieties

In a breast tumor, within the start and stop codons, BRCA1 gene has captured over 200,000 nucleotide bases. The BRCA1 genes carry about 3000 mutations. These mutations are caused by exposure to radiations, chemical or environmental pollutants, viral infection, or genetic inheritance. To attack the mutated nucleotides among the 3000 cells in BRCA1 gene, I could use male hormone, testosterone, and bind multiple radiolabeled aziridine and carbamate ions to attack BRCA1 mutations. By using three-dimensional MRI, I could show how many radiolabeled nucleotides were bound to which mutations. Out of 17 positions available for substitutions on testosterone ring system, there are only three positions, that is, 1, 3, and 17 available for substitution on testosterone ring system. Carl Djerassi [27] had demonstrated that we could activate positions 9 and 10 by reacting with bromoacetamide which introduces a bromo ion on position 10 which could be de-brominated by collidine to introduce a 9,10 double bond which we could further brominate to produce 9,10 dibromo compound. This bromo ion could be replaced by additional aziridine or carbamate ions. I could increase or decrease the number of aziridine and carbamate ions to get the maximum benefit by further brominating positions

15 and 16 to introduce additional aziridine and carbamate moieties.

number of aziridine and carbamate ions to get the maximum benefit.

**11. Ethical issues (the impact of science on society)**

Similarly, I could use the female hormone estrogen and by attaching multiple aziridine and carbamate ions to attack prostate tumor. Since there are 17 positions also available on estrogen ring as well; again, I could increase or decrease the

By 2050, novel drug design would have produced new class of medicine to treat

all known 6000 genes. We would not only produce new treatment but also we would have new food, new fuel, and new medicine to treat every disease known to mankind to protect, preserve, and prolong human life beyond 100 years. This

Our attempt to prolong human life by shutting off the genes of the old age diseases raises several ethical and moral questions. We face the same population problem when we succeed in shutting off genes of all three old age diseases, that is, cancer, cardiovascular disease, and Alzheimer. Most people will live longer and

section discusses the impact of prolonging human life beyond 100 years.

#### *The Rational Drug Design to Treat Cancers DOI: http://dx.doi.org/10.5772/intechopen.93325*

*Drug Design - Novel Advances in the Omics Field and Applications*

with the daily life.

"Cancers" section.

nucleotide bases carrying 1173 genes.

**9. Rationale for designing drugs to treat Alzheimer**

**10. What other cancers should we explore next?**

It is well known that using the TFT dye, which is 3,6-dimethyl-2-(4 dimethlaminophenyl)-benzothiazoline, could be used to stain the plaques and tangles of Alzheimer tissues. Using TFT dye as a carrier for the aziridine and carbamate moieties, we could design drugs to attack the mutated DNA to shut off genes which form plaques and tangles to prevent the progress of Alzheimer. In the above "Cancers" section, I have described in detail how I had used quinone as a carrier for aziridine and carbamate ions in designing AZQ to attack the brain tumor DNA to shut off genes for treating brain cancer. Similarly, the analogs of benzothiazoline dyes could be used to carry aziridine and carbamate moieties to attack the plaque and tangle DNA and shut off genes responsible for causing

Could I use the same rational drug design and introduce a novel method for

and other mental functions such as erosion of attention, thinking, reasoning, visual functions, spatial function, and dementia with memory loss and other cognitive functions resulting in mental impairment which affects to the degree interfering

Recent studies confirm that Alzheimer is an irreversible brain disorder which slowly destroys memory and thinking skills. The damage to the brain is not particularly associated to any specific gene, but the presence of the one form of the apolipoprotein E (APOE) is a suspect gene whose presence does increase a patient's risk for developing Alzheimer. The early onset of Alzheimer is associated with three single gene mutations: first, the presence of an amyloid precursor protein (APP) located on chromosome-21; the presence of presenilin 1 (PSEN1) on chromosome-14 and the presence of presenilin 2 (PSEN2) located on chromosome-1. All three chromosomes are very large and carry hundreds of genes. For example, chromosome-1 is the largest chromosome in the genome. It is made of 163 million nucleotide bases carrying 2610 genes. Chromosome-21 is made of 50 million nucleotide bases carrying 337 genes, while chromosome-14 is made of 109 million

A recent 7 million Utah population study identified two additional genes RAB10 located on chromosome-2 (which is made of 155 million nucleotide bases and carry 1798 genes) and SAR1A gene located on chromosome-10 (which is made of 144 million nucleotide bases and carry 983 genes) associated with the formation of plaques and tangles. Mutations on these genes may be associated with the onset of Alzheimer. Of all the genes on these chromosomes, only five single-gene mutations are associated with the early onset of the Alzheimer, it is the greatest challenge to design drugs to attack only the mutated genes. As I said above in the "Cancers" section, the good news is that the only mutated genes grow rapidly using glucose as a source of energy. Glucose is broken down to produce pyruvic acid. It is the acid which activates the aziridine and carbamate moieties producing powerful carbonium ion which attack N-7 guanine of DNA and shut off only the mutated genes. Other genes are not affected. Using C-14 radiolabeled aziridines, we can identify the mutated gene which form the aziridine/protein complex as described in the

**110**

Alzheimer.

treating breast tumor?

Although mutations on BRCA1 gene located on chromosome-17 (which is made of 92 million nucleotide bases carrying 1394 genes) have been identified years ago responsible for causing breast cancer, we wonder why it has been so difficult to design drugs on rational basis to treat breast cancer. By the time the breast cancer diagnosis is confirmed in a patient, the BRCA1 has accumulated more than 3000 mutations. Genotyping of the blood would also show the existence of many cells carrying mutated cells responsible for creating secondary deposits. It is also believed that by the time breast cancer is confirmed, metastatic cancer cells have already been spread from liver lung on its way to brain. Since all other organs including breast and liver could be removed and replaced by organ transplant except brain, I thought that protecting brain is utmost important to save life. Once AZQ is developed to protect the brain, I could focus on the breast and prostate cancers.

Recent, radiolabeled studies showed that male hormone testosterone has great affinity for female organs like breast, ovary, and fallopian tube cells. On the other hand, estrogen, the female hormone, has great affinity for male prostate gland. By attaching multiple aziridine rings and carbamate ions to both hormones, I could design novel drugs to attack the breast and the prostate cancer. Now, I found that I could go even further by attaching more than four aziridine and carbamate moieties to both male and female hormones.

In a breast tumor, within the start and stop codons, BRCA1 gene has captured over 200,000 nucleotide bases. The BRCA1 genes carry about 3000 mutations. These mutations are caused by exposure to radiations, chemical or environmental pollutants, viral infection, or genetic inheritance. To attack the mutated nucleotides among the 3000 cells in BRCA1 gene, I could use male hormone, testosterone, and bind multiple radiolabeled aziridine and carbamate ions to attack BRCA1 mutations. By using three-dimensional MRI, I could show how many radiolabeled nucleotides were bound to which mutations. Out of 17 positions available for substitutions on testosterone ring system, there are only three positions, that is, 1, 3, and 17 available for substitution on testosterone ring system. Carl Djerassi [27] had demonstrated that we could activate positions 9 and 10 by reacting with bromoacetamide which introduces a bromo ion on position 10 which could be de-brominated by collidine to introduce a 9,10 double bond which we could further brominate to produce 9,10 dibromo compound. This bromo ion could be replaced by additional aziridine or carbamate ions. I could increase or decrease the number of aziridine and carbamate ions to get the maximum benefit by further brominating positions 15 and 16 to introduce additional aziridine and carbamate moieties.

Similarly, I could use the female hormone estrogen and by attaching multiple aziridine and carbamate ions to attack prostate tumor. Since there are 17 positions also available on estrogen ring as well; again, I could increase or decrease the number of aziridine and carbamate ions to get the maximum benefit.
