Targeting Cell Nucleus Structures

Replication, the process by which identical copies of DNA can be made so that 

Transcription the process by which the genetic information contained in DNA is 

These three fundamental processes are central targets in drug design. 

As a putative receptor, nucleic acids are suitable molecules. Nucleic acids, unlike alkyl chain lipids, are not bland rather, they are reasonably complicated molecules in terms of possessing heteroatoms and hydrogen-bonding donors and acceptors. Such complexity affords a diversity of opportunities for designing molecules capable of unique interactions with DNA or RNA. Given the importance of nucleic acids to heredity and 

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Figure 7.1 Drug targets at the level of cellular structure. The mammalian cell presents a variety of druggable targets. The most important ones are located at the level of the cell membrane. Within the cell, cytoplasmic organelles, such as mitochondria, are beginning to be exploited as potential drug targets. The nucleus, at the center of the cell, is an important target for the development of antineoplastic agents for the treatment of cancer.

The cell nucleus is another important source of druggable targets. Surprisingly, the nucleus is not as important to the survival of an individual cell as are many of the cytoplasmic organelles. A cell can live without its nucleus, it just cannot reproduce. (Mature adult human red blood cells, for example, do not have nuclei.) On the other hand, a cell cannot live without its mitochondria. Therefore, the cell nucleus is an important structure to target when designing drugs for diseases in which one wishes to stop cellular reproduction (e.g., cancer, viral or bacterial infections). 

The triphenylethylene antiestrogens (Fig. 46.9) are structurally related to the stilbene family of estrogens and exhibit high affinity for the ER. They prevent translocation of the estrogen-receptor complex into the nucleus of target cells and interfere with the binding of the receptor-hormone complex to the acceptor site of the chromatin (29,30). 

The model described above Is based on the assumption that lethal damage corresponds to point-like events, where point-llke is meant in a biological sense, i.e., a point corresponds to the size of the smallest relevant biological structure, assumed to be the DNA strand and thus a size of a few nanometers. The critical, sensitive target for inactivation, I.e., the DNA, Is assumed to be homogenously distributed throughout the cell nucleus, and no specific substructure has been assumed. 

Another level of metabolism peculiar to mammals that may be involved in mutagenesis concerns hormones. The biological action of hormones begins at the level of the chromosome. Steroids bind to a receptor in the cytoplasm of hormone-target cells the hormone-receptor complex diffuses into the nucleus and induces a modification in chromatin structure as indicated by increased nuclear binding of isotopically labeled actinomycin Thyroxine diffuses... 

Fig. 2.2-1. A neutron capture event seen in relation to the size of the target. Electron microscopic image of uncontrasted tumor tissue, stained for boron by antibodies. The smaller structure surrounded by clusters of dots is the nucleus. The thin structure lined with dots is the cell membrane. The dots are gold particles attached to the antibodies which are specifically directed against the...

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