SUBSTITUTIONS OF THE 3- AND 5-IODO GROUPS
As explained above, the 3- and 5-iodo groups are important because of their size.  Replacement of these atoms by other large bulky groups will result in the retention of activity, while replacement of these atoms by smaller groups will decrease activity.  Replacement of an iodine atom by a hydrogen atom (the smallest atom) will abolish activity.  This explains why rT3 and T2 are inactive.  The following general rule can be applied:  as the size of the substituents at positions 3 and 5 increase, the ability of the molecule to "lock in" the active conformation also increases, thus allowing for enhanced or optimum activity.  The following two examples examine how different substituents might affect activity.

Analog 1

• The 3-iodo group has been replaced with a 3-fluoro group (yellow atom, designated as F[11]).  This is the side view of the molecule.
• Using the bottom and right rotation bars, observe the rear and overhead views.
• QUESTION 2:  Judging by what you see on the screen and what you have learned in this exercise, how would you expect the activity of this thyroid analog to compare with the activity of thyroxine?

Although not required, some students may wish to rotate the molecule about the O[1]-C[2] bond as was previously done with levothyroxine.  To do this switch to Ball and Stick mode, click the O[1] atom, verify that a white ring highlights the O[1] atom, switch back to the Space Filling mode,  rotate about the selected bond using the left rotation bar, and again examine the overhead, side and rear views.

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