Zetekitoxin AB

Kate Wilkin Laura Graham Background of Zetekitoxin AB

 Potent water-soluble guanidinium toxin extracted from the skin of the Panamanian golden frog, Atelopus zeteki.  Identified by Harry S. Mosher and colleagues at Stanford University, 1969.  Originally named 1,2- atelopidtoxin. Progression

 1975 – found chiriquitoxin in a Costa Rican Atelopus frog.  1977 – Mosher isolated 2 components of 1,2-atelopidtoxin.  AB  major component, more toxic  C  minor component, less toxic  1986 – purified from skin extracts by Daly and Kim.  1990 – the major component was renamed after the frog species zeteki.

Classification Structural Identification Structural Identification - IR

Cm -1 Functional Groups

1268 OSO3H 1700 Carbamate 1051 – 1022 C – N Structural Identification – MS Structural Identification – 13C

Carbon Number Ppm Assignment 2 ~ 159 C = NH 4 ~ 85 Quaternary Carbon 5 ~ 59 Tertiary Carbon 6 ~ 54 Tertiary Carbon 8 ~ 158 C = NH Structural Identification – 13C

Carbon Number Ppm Assignment

10 55 / 43 C H2 - more subst. on ZTX

11 89 / 33 Ring and OSO3H on ZTX 12 ~ 98 Carbon attached to 2 OH groups 19 / 13 70 / 64 ZTX: C – N STX: C – C 20 / 14 ~ 157 Carbamate Structural Identification – 13C

Carbon Number Ppm Assignment 13 156 Amide

14 34 CH2 15 54 C – N 16 47 Tertiary Carbon 17 69 C – O – N 18 62 C – OH Structural Identification - 1H Synthesis

Synthesis

 O. Iwamoto and Dr. K. Nagasawa  Tokyo University of Agriculture and Technology.  October 10th, 2007  “Further work to synthesize natural STXs and various derivatives is in progress with the aim of developing isoform-selective sodium-channel inhibitors”

Therapeutic Applications

 Possible anesthetic, but has poor therapeutic index.  Toxicity occurs before therapeutic effects.  Possible combinations with other drugs to create a larger window between toxic and effect doses.  Research done on STXs effect on the sciatic nerves in rats.  Research done on ZTXs effect on the brain cells.

Structure and Toxicity

 Guanidinium groups essential for binding and must be in charged state.  Carbamoyl chain  Zetekitoxin AB has highest affinity for sodium channels.

Research and the Environment

 Other sources of the toxin?  Absorbed from algal blooms?  Produced internally?  How to improve detection methods?  Spread awareness.  Sensitivity to toxin varies, why?  Biosynthetic profits?  Obviously a defense.  Other reasons?

The End.. almost http://www.youtube.com/watch ?v=ZOp3rFQvgPI

Citations

1) Iwamoto, O., Koshino, H. Hashizume., D., Nagasawa, K. (2007). Total synthesis of (-)-decarbamoyloxysaxitoxin. Angew. Chem. Int. Ed. 46, 8625-8628.

2) Llewellyn, L.E. (2006). Saxitoxin, a toxic marine natural product that targets a multitude of receptors. Nat. Prod. Rep. 23, 200-222.

3) Mosher, H.S., Fuhrman, F.A., Buchwald, H.D., Fischer, H.G. (1964). Tarichatoxin- tetrodotoxin: a potent neurotoxin. Science. 144, 1100-1110.

4) Yang, L., Kao, C.Y. (1992). Actions of chiriquitoxin on frog skeletal muscle fibers and implications for the tetrodotoxin/saxitoxin receptor. J. Gen. Physiol. 100, 609-622.

5) Yotsu-Yamashita, M., Kim, Y.H., Dudley, S. C. Jr., Choudhary, G., Pfahnl, A., Oshima, Y., Daly, J.W. (2004). The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Atelopus zeteki: a potent sodium-channel blocker. PNAS. 101, 4346-4351.

6) Yotsu-Yamashita, M. (2006). Spectroscopic study of the structure zetekitoxin AB. Top Heterocycl. Chem. 5, 53-63.