Tamoxifen derivatives.

The basic tamoxifen skeleton can be modified as to maximise the oestrogen inhibiting properties of the molecule. As mentioned earlier 4-Hydroxytamoxifen binds to oestrogen receptor sites up to 500 times more effectively. The substitution of differing groups on to the basic structure can have a wide range of effects. The main positions which are most commonly substituted are shown below.

Many derivatives have been constructed all with differing amounts of success. The cancer inhibiting ability has also been of a wide range. The common functional groups which have been substituted at a variety of positions include Iodo,Bromo, Chloro, Ether, Aryl, Alkyl, Acid and Amine groups.

An excellent article which discusses the effectiveness of most substituants is Day ( J.Med.Chem,1991,842-851). In this article the author reports findings on substituant which include -OCH3, -OCH2Ph, OH and various alkyl groups and their effectiveness on cancerous growths.

The conclusion of his research was that only 4-Hydroxytamoxifen showed a binding affinity greater than that of Tamoxifen.The article describes the synthetic routes by which these derivatives can be produced and again includes some similar reactions to those mentioned in my earlier synthesis section. i.e. examples of use of dehydration to form double bonds via E1 mechanisms and common use of Grignard reagents.

Above :- Structrural formula of both Left 4-Hydrotamoxifen and Right 4-Iodotamoixfen.

Below: Molecular models of the corrosponding derivitives.

There has also been some interest shown in the dichloroderivitives of Tamoxifen.Such compounds do not contain a double bond in the familiar Tamoxifen strutrure. These are fromed via substitution of chlorine atoms across the double bond.

Below : Most recent developments have seen that research has been commissoned into a similar compound called Raloxifene which again shows antiestrogen activity and is currently being investigated (Early 1999)

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Huw Tanner.Undergraduate Year 2 .Imperial College of Science,Technology and Medicine.

CIT Project

Study of Tamoxifen.