Daly John W, Garraffo H Martin, Spande Thomas F, Clark Valerie C, Ma Jingyuan, Ziffer Herman, Cover John F
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-0820, USA.
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11092-7. doi: 10.1073/pnas.1834430100. Epub 2003 Sep 5.
Dendrobatid poison frogs readily accumulate alkaloids from diet into skin, where such compounds serve as a chemical defense against predators. Arthropods seem to be the source of decahydroquinolines (DHQs), several izidines, coccinellines, spiropyrrolizidines, pumiliotoxins (PTXs), and allopumiliotoxins (aPTXs). A DHQ iso-223F, and PTX (+)-251D were fed to poison frogs of the dendrobatid genera Dendrobates, Epipedobates, and Phyllobates. The two alkaloids were accumulated in skin unchanged except for the three species of Dendrobates, where approximately 80% of accumulated PTX (+)-251D was stereoselectively hydroxylated to aPTX (+)-267A. The unnatural enantiomer PTX (-)-251D was accumulated efficiently when fed to Dendrobates auratus, but was not hydroxylated. The enantiomers of PTX 251D and their desmethyl analogs were synthesized from N-Boc-protected (-)- and (+)-proline methyl esters. Both PTX (+)-251D and aPTX (+)-267A proved to be potent convulsants in mice, with (+)-267A being approximately 5-fold more toxic than (+)-251D. Both alkaloids were hyperalgesic at the site of injection. The unnatural PTX (-)-251D caused no overt effect in mice. Thus, the evolutionary development of a pumiliotoxin 7-hydroxylase would have provided frogs of the genus Dendrobates with a means of enhancing the antipredator potency of ingested PTXs.
箭毒蛙能轻易地将饮食中的生物碱积累到皮肤中，这些化合物可作为抵御捕食者的化学防御物质。节肢动物似乎是十氢喹啉（DHQs）、几种异吲哚生物碱、瓢虫生物碱、螺吡咯烷生物碱、 pumiliotoxins（PTXs）和去甲 pumiliotoxins（aPTXs）的来源。将一种DHQ异构体 - 223F和PTX（+） - 251D投喂给箭毒蛙属（Dendrobates）、叶毒蛙属（Epipedobates）和叶蛙属（Phyllobates）的箭毒蛙。除了三种Dendrobates蛙外，这两种生物碱在皮肤中未发生变化地积累，在这三种Dendrobates蛙中，积累的PTX（+） - 251D约80%被立体选择性地羟基化为aPTX（+） - 267A。当将非天然对映体PTX（ - ） - 251D投喂给绿背箭毒蛙（Dendrobates auratus）时，它能有效积累，但未被羟基化。PTX 251D的对映体及其去甲基类似物由N - Boc保护的（ - ） - 和（+） - 脯氨酸甲酯合成。PTX（+） - 251D和aPTX（+） - 267A在小鼠中均被证明是强效惊厥剂，其中（+） - 267A的毒性比（+） - 251D高约5倍。两种生物碱在注射部位均具有痛觉过敏作用。非天然的PTX（ - ） - 251D在小鼠中未产生明显影响。因此，pumiliotoxin 7 - 羟化酶的进化发展为Dendrobates属的青蛙提供了一种增强摄入的PTXs抗捕食能力的方法。
