- Derivatives -

       Tetrodotoxin (TTX) usually exists as a mixture of its derivatives. Due to variations in its
structure, some of these analogues are difficult to detect. It derivatives can be classified under
two categories – naturally occurring and synthetic derivatives.

Naturally Occurring Derivatives
- Isolated from pufferfish, newts and frogs
- Detected by spectroscopic methods
Analogous of Tetrodotoxin has been identified by a combination of liquid chromatography
and electrospray ionization mass spectrometry. This method involves a reversed phase
column with long carbon chains and a mobile phase including an ion-pair reagent such
as ammonium heptafluorobutyrate.

Synthetic Derivatives (prepared by chemical modification of the structure)
There are various synthetic routes to obtain derivatives of Tetrodotoxin. One of the most
well-known techniques to achieve this is via the Pfitzner-Moffatt oxidation. 2 examples of
this method are shown below. Through the Pfitzner-Moffatt reaction, 5 derivatives were also
prepared by covalent attachment of either lysine, glycine, beta-alanine or ethylenediamine
to the oxidized toxin.

Example 1: 2 step Pfitzner-Moffatt oxidation



Step 1
Reagents : H2O2, FeSO4.7H2O
Solvents : H2O, AcOH

Step 2
Reagents : NaBT4
Solvents : AcOH,H2O,MeCN

Example 2: 1 step Pfitzner-Moffatt oxidation


Reagents : DMSO, H3PO4, DCC
Solvents : CF3COOH

Besides the Pfitzner-Moffatt oxidation, TTX derivatives can also be obtained by other methods.
The diagram below shows 4 ways of synthesizing 7 different TTX derivates, and their respective yields.

"Synthetic TTX derivatives"
A, 11-oxoTTX and TTX-11-carboxylic acid; B, 11-norTTX-6,6-diol, 11-norTTX-6(S)-ol,
and 11-norTTX-6(R)-ol; C, tetrodonic acid; D, TTX-8-O-hemisaccinate.
- http://jpet.aspetjournals.org/cgi/content/full/289/3/1688

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