Many anticancer drugs work by disrupting the function of DNA (deoxyribonucleic acid) in the cancer cells thereby preventing cell division from occuring. DNA has a double helical structure, with two strands held together by hydrogen bonds between complementary base pairs. It carries a negative charge at cell pH and is found in the nucleus of all cells.
The compound cis-platin has a square planar geometry as this shape minimizes repulsive interactions between electrons in the d-orbtitals. Consequently it can exist as cis and trans isomers.
It does not work if the compound is trans-platin. This is because it no longer has the unique property of two chlorine on one side.
D.8.2 Discuss the importance of chirality in drug action
Although the two enationmers of a molecule usually have identical chemical properties, they can react differently in the presence of a chiral environment, such as with the enzymes and receptors in the body. Most enantiomers only have one that is biologically active and their physiological properties are very different.
The major impetus for this research activity in stereochemistry came from teh thalidomide tragedy. The drug was manufactured and sold as a racemic misture, It was discovered later that only the (R) isomer induced sleep and calmness in pregnant women, Its enantiomer, the (S) form, was teratogenic - it was able to cross the placenta and produce serious deformities in the fetus.
D.8.3 Explain the importance of the beta-lactam ring action of penicillin
The strucutre of penicillin, as determined by X-ray crystallography in 1945, contains a nucleus of a five-membered ring containing a sulfur atom known as thiazolidine, attached to a four-membered ring containing a cyclic amide group known as beta-lactam.
The bond angles in this ring are reduced to about 90 degree celcius despite the fact that because they have sp2 and sp3 hybridized atomic orbitals, the atoms in the ring seek to form bonds with angles of 120 and 109.5 respectively. This puts a strain on the bonds, effectively weakening them. Consequently, the ring breaks relatively easily and this is the key to the molecule's biological activity.
The action of these beta-lactam antibiotics is to disrupt the formation of cell walls of bacteria by inhibiting a key bacterial enzyme, transpeptidase, As the enzyme approaches the enzyme, the high reactivity of the amide group in the ring causes it to irreversibly bind near the active site of the enzyme as the ring breaks. Inactivation of the enzyme in this way blocks the process of cell wall construction within the bacterium because it prevents polypeptide cross-links forming between the mucopeptide chains. Without these strengthening links, the cell wall is unable to support the bacterium, which bursts and die.
D.8.4 Explain the increased potency of diamorphine (heroin) compared to morphine
Morphine, the principle drug derived from opium, is not able to cross the blood-brain barrier very effeciently due to its two polar -OH groups. Heroin (diamorphine), on the other hand, in which the two -OH groups have been replaced by ethanoate (ester) groups shown in green here, is much less polar.
This reduction in polarity of the molecule enables it to cross the blood-brain barrier more easily. Thus, heroin has a much greater potency than morphine; it reaches brain cells faster and in higher concentration. It is more active by a factor of two. Note that this also applies to its greater side-effects as well as to its characteristics of tolerance and dependence.
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