From Forest Floors to Pharmacology: Elucidating Millipede Defensive Alkaloids for Drug Discovery

dc.contributor.authorBanks, Margaret P.en
dc.contributor.committeechairMevers, Emily Elizabethen
dc.contributor.committeememberAllen, Kylie Dawnen
dc.contributor.committeememberLowell, Andrew Nesemannen
dc.contributor.committeememberGentry, Emily Christineen
dc.contributor.departmentChemistryen
dc.date.accessioned2025-04-03T08:00:52Zen
dc.date.available2025-04-03T08:00:52Zen
dc.date.issued2025-04-01en
dc.description.abstractMillipedes are some of the oldest animals on earth, evolving over 400 million years ago (mya). The subterclass, Colobognatha evolved 99 mya and are largely understudied compared to other classes of millipedes. Like most other millipede classes, Colobognatha possess repugnatorial glands, which store alkaloids as defensive compounds. However, they have also evolved unique characteristics that set them apart from all other millipedes, including distinct anatomy, group behavior, brood care, and the production of terpenoid alkaloids. Prior to 2020, only 11 alkaloids were known. Herein, a total of 25 new terpenoid alkaloids are reported coming from three different genera, all belonging to the same order. Key findings include the discovery of indolizine and quinolizidine alkaloids (e.g., hydrogosodesmine, homogosodesmine and homo-hydrogosodesmine) from the defensive secretions of various Brachcybye species (Chapter 2), the discovery of the ischnocybine alkaloids from the defensive secretions of Ischnocybe plicata (Chapter 3), and the discovery of the andrognathines and andrognathanols from the defensive secretions of Andrognathus corticarius (Chapter 4). The structure elucidation of each utilized modern techniques, including 2D NMR, HRMS, DFT, ECD, chemical synthesis, and Mosher's analysis. Many of these new alkaloids represent new natural product classes with carbon backbones that are unprecedented in the literature. Biological and ecological evaluation revealed the new alkaloids deter ants, a common predator to millipedes (Chapter 3), and this led to the discovery that a subset of the alkaloids potently binds to sigma-1 receptor (ischnocybine A: Ki 14 nM), while others bind to sigma-2 (homo-hydrogosodesmine hydrate: Ki 260 nM). Furthermore, ecology studies revealed that the alkaloid production is conserved over large geographical regions, accumulated as the millipedes gain segments and are actively secreted through the ozopores when physically agitated. These discoveries provide insights into a potential biosynthetic pathway shared by all Platydesmida millipedes and support the hypothesis that alkaloid biosynthesis in this order is evolving toward greater simplicity.en
dc.description.abstractgeneralMillipedes are some of the oldest animals and have been roaming Earth for over 400 million years. These small, soft-bodied creatures live beneath decaying debris on forest floors and defend themselves from predators using unique chemical secretions. This dissertation focuses on understanding the chemical composition of the defensive secretions of a remarkable group of millipedes, the Colobognatha, which are known for their unusual feeding habits and social behaviors. Through this research, a total of 25 new distinct compounds were discovered from defensive secretions of four different millipede species. A subset of these compounds was determined to bind to a neuroreceptor and therefore may be useful in the treatment of non-addictive pain, Parkinson's, and Alzheimer Disease. The summation of this work sheds light on the diversity of millipede defensive secretions and provides insights into how these intriguing compounds are made by the millipede, as well as how they have evolved over millennia. This work may potentially lead to new treatments to treat a variety of neurological diseases.en
dc.description.degreeDoctor of Philosophyen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:42516en
dc.identifier.urihttps://hdl.handle.net/10919/125127en
dc.language.isoenen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectMillipede defenseen
dc.subjectnatural productsen
dc.subjectneuromodulatorsen
dc.subjectterpenoid alkaloidsen
dc.titleFrom Forest Floors to Pharmacology: Elucidating Millipede Defensive Alkaloids for Drug Discoveryen
dc.typeDissertationen
thesis.degree.disciplineChemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.nameDoctor of Philosophyen

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