Module 1: Introduction to Enediyne Class of Natural Products

Lecture 1 : History of Discovery of Enediynes and History of Cancer

1.1. History of Discovery of Enediynes

1.1.1. Introduction

Deoxyribonucleic Acid (DNA), discovered in cell nuclei in 1868 by Fritz Meischer a Swiss Physicist, holds all the information of life within biological systems from which the blueprint of life is built by mother nature similar to the information hidden in a brick that determine the full blueprint of the entire building. Discovering the modern structure of DNA, in 1953, Watson and Crick were subsequently awarded the Nobel Prize in 1962. DNA is involved in storage and transmission of genetic information. Everything about us including our hair/eye color, body type, talent/intelligence, prone to diseases, and response to a particular medication, etc. is contained within this incredible creation by the ingenious job of Mother Nature, the DNA. The blueprint or genetic code is stored in our DNA that replicates at each cell division. Therefore, every cell contains information about the entire organism. DNA is a double stranded helix made up of millions of base fragments. A single DNA chain may be up to 12 centimeters in length and contain 250 million base pairs.
Cell division is essential for an organism to grow. During this cell division process, DNA makes its own copy. So two daughter cells will have the same genetic information as their parent. This process of making perfect copy of DNA by DNA polymerase enzyme is known as DNA replication. In brief, DNA replication occurs as per the scheme 1. Thus, in solution, DNA unwinds to give single strands, which bond with free bases in solution, to form complimentary strands, thereby reproducing another DNA molecule. Following are the main steps involved in DNA replication carried out by DNA polymerase
(Scheme 1).

Scheme 1. DNA replication within our cells.

Despite the enormous size of DNA molecules, the replication sequence is carried out in relative harmony with errors occurring only about once in every 10-100 billion base pairs. Although errors do not occur often in a numerical sense; however, any error may interrupt the genetic code. In such a case, if left unrepaired the error by cell’s repairing machinery an incorrect transmission of genetic information by DNA in replication of these 250 million may lead to a mutation. Such mutations are also caused upon exposure to light, radiation, viruses, transposons and mutagenic chemicals.

Many mutations are harmless and do not affect our blueprint. However, some mutations may lead to uncontrolled replication. In most DNA sequences, our body knows when replication should be controlled, but when mutations occur, the body is overridden, and replication does not stop. The process of cell division is a very tightly controlled process and occurs in the body only to the extent needed in any particular situation. During the process of cell division if nncontrolled replication of the mutated DNA occurs, the daughter cell may acquire some genetic mutation that would alter the cell division control mechanisms of that cell. This altered cell no longer listens to the control signals for cell division and may continue to divide and multiply. The cells replicate so rapidly and continuously that they will have a very high error rate in DNA replication. The population of oncogenic cells is highly varied and some are able to avoid normal tumor necrosis factors and T cell mediated destruction. This differential survival from a varied population of replicating cells makes for a rapid evolution, resulting in a tumor with abnormal numbers of chromosomes, an over expression of telomerase to resist cell death, and a lack of response to normal growth regulating factors. The cells then continue to replicate without recognition of normal tissue cell-to-cell boundaries so they become invasive. This uncontrolled cell division and growth ultimately results in malignant tumors, and cancer. Multiple genetic events are involved in the development of most malignancies.
In an effort to fight this uncontrolled growth of cells, chemists have been trying to find molecules to arrest formation of the malignant tumors. These molecules are known as
antitumor antibiotics.