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Good variants are responsible for our evolution, and abnormal variants are responsible for causing diseases. Using restriction enzymes (molecular scissors) like EcoR1, we can cut, paste, and copy a gene (conduct genetic engineering) and prepare a chart (called restriction site map) of all 6000 variants amoxicillin epocrates responsible for causing all 6000 diseases.

By comparing the sequence of a genes from the chart, we can predict which specific gene variant is expected to cause which disease.

As cells grow, the mutations accumulate and defects in genotype manifests in phenotype.

By using MRI (magnetic resonance imaging which provides three-dimensional image) method, one could see the progressive microscopic abnormal changes in the nucleotide bases and predict the onset of a disease.

The three-dimensional MR imaging could serve as a diagnostic technique. Once the diagnosis is confirmed, drug design must begin to treat the disease. We take the MRI of all 220 tissues of a healthy person and during his annual medical checkup compare the present MRI with the previous years’ MRI to see any unusual microscopic changes predicting diseases. Once identified, the next logical step is to design drugs to shut off mutated genes to prevent diseases.

Genetic disorders can be caused by a mutation in one gene (monogenic disorder), by mutations in multiple genes (multifactorial inheritance disorder), by a combination of gene

mutations

What specific nucleotide damage forming the codon is responsible for causing catastrophic diseases?

By comparing the mutations in a DNA sequence (genotype), we can predict the onset of a disease in human (phenotype).

The microscopic changes not detected by observations can be confirmed by three-dimensional MRI technique, which will diagnose diseases long before the symptoms appear. To some degree, we

have

The sequencing of the human genome provides rational approach to the quality control of the population.

We have good news for those families who are suffering from severe heritable diseases generations after generations.

Some of those rare allele diseases are mental diseases such as Parkinson, Huntington, schizophrenia, bipolar disorder, etc. Those family members

can

Suppose the sequenced cell identify abnormal mutations when implanted will produce an incurably blind child or mentally retarded child. Is there a reason to bring this child into this intensely competitive world?

To complete his education from age 5 to 25 years, when he completes his education and receives his Doctorate Degree, a child has to take several tests.

If he fails one test, he is thrown out of the success train. No matter how painful it is on either religious or moral ground, we must ask ourselves a simple question. Does this fertilized ovum produce an acceptable member of the human society? If the answer is no, then we must throw out the defected ovum and use a new ovum. Should we sequence and select a cell for implantation which is free from all harmful mutations? Before the development of antibiotics, most people died of infectious diseases around age 50.

First, antibiotics, penicillin (discovered by Alexander Fleming), was used for treating wounds before the WWII.

As I said above, enormous funds were made available by the army to develop large-scale antibiotics to treat wounded soldiers returning from the battle ground during WWII. During the following decades, novel class of aminoglycoside antibiotics were discovered, which are valuable therapeutic agents.

Some of them are streptomycin, neomycin, kanamycin, paromomycin, apramycin, tobramycin, amikacin, netilmicin, gentamicin, etc. Dozens of their water/fat-soluble derivatives were synthesized.

They are considered broad spectrum antibiotics because they inhibit the growth of both Gram-negative and Gram-positive bacteria causing deadly diseases and save human life.

All aminoglycoside antibiotics are relatively small, basic, and water-soluble molecules that form stable salts. Most aminoglycoside antibiotics are products of fermentation of filamentous actinomycetes of the genus Streptomyces . Nowadays, people rarely die of

infectious

Those who live beyond 70 are faced with three major old age diseases, which are responsible for causing the death of most patients during their lifetime and they are cancers, cardiac diseases, and Alzheimer. These are genetic diseases and could be treated either by gene therapy (using CRISPER technology by replacing bad gene with the good gene using CRISPER-Cas9) or by drug therapy. There are about 3000 monogenic diseases and could be treated by replacing the defected gene with good gene, that is, by gene therapy or

designing

Gene therapy cannot be applied to treat multiple genetic defects such as Alzheimer, cancer, and cardiovascular diseases.

Drug therapy could be used to develop novel treatments.

Recently completed 1000 Human Genome Project identify with precision and accuracy the genes responsible for causing these diseases. It is now possible to design drugs to shut off these genes and save human life. Genes code for proteins and a mutated gene codes for abnormal proteins resulting in these diseases.

Cancer is the leading cause of death and has surpassed the death of cardiovascular diseases. Over 636,000 people died of

cancer

Once diagnosed by gene sequencing, the next step is to design drug to shut off those genes. All three old age diseases, that is, cancer, cardiovascular diseases, and Alzheimer carry multiple mutated genes responsible for causing these diseases. In each of the above three diseases, it is the mutated genes that code for wrong protein which causes

these

should

Most of these variants are dispersed across the genome and do not cluster on one specific chromosome. Drugs are designed to seek out the specific malignant gene, which replicates faster producing acids.

Aziridines and carbamate moieties are sensitive to acid.

Drugs carrying the aziridines

and

It does not matter whether they are clustered or dispersed across genome.

The supreme intellect for drug design is Ross, an Englishman, who is a Professor of Chemistry at the London University. Professor WCJ Ross is also the Head of Chemistry Department at the Royal Cancer Hospital, a postgraduate medical center of the London University. Ross was the first person who designed drugs for treating cancers.

He designed drugs to cross-link both strands of DNA that we inherit one strand from each parent.

Cross-linking agents such as nitrogen mustard are extremely toxic and were used as chemical weapon during the First World War. More toxic derivatives were developed during the Second World War. Using the data for the toxic effect of nitrogen mustard used during the First World War, Ross observed that soldiers exposed to nitrogen mustard showed a sharp decline of white blood cells (WBC) that is from 5000 cell/CC to 500 cells/CC. Children suffering from childhood leukemia have a very high WBC count over 90,000 cells/CC. In sick children, most of the WBCs are premature, defected, and unable to defend the body from microbial infections. Ross rationale was that cancer cells divide faster than the normal cell, by using nitrogen mustard to cross-link both strands of DNA, one can control and stop the abnormal WBC cell division in leukemia

patients

Professor Ross was the first person to synthesize a large number of derivatives of nitrogen mustard. By using an analog of nitrogen mustard, called chlorambucil [9], he was successful in treating

childhood

In America, two physicians named Goodman and Gilman from the Yale University were the first i need a prescription for amoxicillin to use nitrogen mustard to treat cancer in humans. Nitrogen mustards and its analogs are highly toxic. Ross was a chemist; over the years, he synthesized several hundred derivatives of nitrogen mustard molecules to modify toxicity of nitrogen mustard [10, 11, 12, 13, 14]. Although analogs of nitrogen mustard are highly toxic, they are more toxic to cancer cells and more cancer cells are destroyed than the normal cells. Toxicity is measured as the chemotherapeutic index (CI), which is a ratio between toxicity to cancer cells versus the toxicity to normal cells. Higher CI means that the drugs are more toxic to cancer cell.

Most cross-linking nitrogen mustard have a CI of 10, that is, they are 10 times more toxic to cancer cells.

Some of the nitrogen mustard analogs Ross made over the years are useful for treating cancers such as chlorambucil for treating childhood leukemia (which brought down the WBC level down to 5000/CC).

Childhood leukemia is the name of a disease occurs in children only.

Chlorambucil made

Ross

6.2 The discovery of AZQ (US Patent 4,146,622) for treating brain cancer.

At the London University, I was trained as an organic chemist in the Laboratory of Professor WCJ Ross of the Royal Cancer Hospital, a postgraduate medical center of the London University.

After working for about 10 years at the London University, I moved to America when I was honored by the Fogarty International Fellowship Award by the National Institutes of Health, NIH, and the National Cancer Institute, NCI, of the buy amoxicillin 875 mg USA. NIH has been my home for over a quarter of a century; I designed drugs to shut off mutated genes.

All three common allele diseases have genetic origin.

The rationale I used to synthesize anticancer drugs could be used to treat the other two old age diseases like Alzheimer and cardiovascular diseases. In the following sections, I will describe in detail how anticancer drug like AZQ was designed to shut off glioblastoma genes which cause brain cancer in humans. Using the same rational, we will consider how each of the other two diseases, namely, cardiovascular disease and Alzheimer could be treated by shutting off their genes to save human life: The order of these diseases are arranged based on the level of funding provided by NIH specifically by the NCI (National Cancer Institute). As I said above, Professor Ross was designing drugs to attack both strands of DNA simultaneously by cross-linking using nitrogen mustard analogs, which are extremely toxic. As a part of my doctoral thesis, I was assigned a different path. Instead of cross-linking DNA, I am to design drugs to attack only one strand of DNA. Over the years, I made over 100 dinitrophenyl aziridine derivatives. One of them is dinitrobenzamide (CB1954) which gives a CI of 70, highest ever recorded.

CB1954 wipes out a solid tumor by attacking the DNA of Walker carcinoma 256, a solid aggressive tumor in rat. Nitrogen mustards are highly toxic because they have neither specificity nor selectivity.

They attack all dividing cells whether they are normal or abnormal. On the other hand, the analogs of aziridines and carbamates remain inactive in the basic and neutral media.

They become activated only in the presence of acidic media. I used a simple rationale, the aziridine attacks DNA in acidic medium, particularly the N-7 guanine.

The dye dinitrobenzamide has great affinity for Walker tumor [16, 17, 18].

The aziridine dinitrobenzamide (CB1954) stains the tumor.

As the tumor grows, it uses glucose as a source of energy.

The ring opens to generate a carbonium ion, which attacks the most negatively charged N-7 guanine of DNA shutting off the Walker carcinoma gene in rat.

To continue my work, I was honored with the Institute of Cancer Research Post-Doctoral Fellowship Award of the Royal Cancer Hospital of London University.

To increase the toxicity of CB1954 to Walker carcinoma, I made additional 20 analogs as a postdoctoral

fellow

generating

Cancer

Institutes

One day, I came across a paper which described that radiolabeled methylated quinone cross the blood-brain barrier in mice. When injected in mice, the X-ray photograph showed that the entire radioactivity was concentrated in the mice’s brain within 24 hours. I immediately realized that glioblastoma multiforme, the brain tumor in humans, is a solid aggressive tumor like Walker carcinoma in rats. I decided to use quinone moiety as a carrier for aziridine rings to attack glioblastomas. By introducing an additional carbamate moiety, I could increase its toxicity several folds. I planned to use this rational to translate animal work to human by introducing multiple aziridine and carbamate moieties to the quinone to test against glioblastomas in humans.

Attaching two aziridines and two carbamate moieties to quinone, I made AZQ.

By treating brain cancer with AZQ, we observed that glioblastoma tumor not only stop growing but also start shrinking.

I could take care of at least one form of deadliest old age cancers, that is, glioblastomas.

Literature search showed that AZQ is extensively studied.

As I said above, glioblastoma, the brain cancers, is a solid and aggressive tumor and is caused by mutations on several chromosomal DNA. Mutations on DNA are the result of damaging DNA nucleotides by exposure to radiations, chemical and environmental pollution, viral infections, or genetic inheritance. The other factors responsible for causing DNA mutations are due to the fast rate of replication of DNA. coli grows so rapidly that within 24 hours, a single cell on a petri dish forms an entire colony of millions when incubated on the agar gel.