Metabolic Soft Spot and Pharmacokinetics: Functionalization of C-3 Position of an Eph–Ephrin Antagonist Featuring a Bile Acid Core as an Effective Strategy to Obtain Oral Bioavailability in Mice

UniPR129, an L-β-homotryptophan conjugate of the secondary bile acid lithocholic acid (LCA), acts as an effective protein-protein interaction (PPI) inhibitor of the Eph–ephrin system but suffers from a poor oral bioavailability in mice. To improve UniPR129 bioavailability, a metabolic soft spot, i.e., the 3α-hydroxyl group on the LCA steroidal ring, was functionalized to 3-hydroxyimine. In vitro metabolism of UniPR129 and 3-hydroxyimine derivative UniPR500 was compared in mouse liver subcellular fractions, and main metabolites were profiled by high resolution (HR-MS) and tandem (MS/MS) mass spectrometry. In mouse liver microsomes (MLM), UniPR129 was converted into several metabolites: M1 derived from the oxidation of the 3-hydroxy group to 3-oxo, M2–M7, mono-hydroxylated metabolites, M8–M10, di-hydroxylated metabolites, and M11, a mono-hydroxylated metabolite of M1. Phase II reactions were only minor routes of in vitro biotransformation. UniPR500 shared several metabolic pathways with parent UniPR129, but it showed higher stability in MLM, with a half-life (t1/2) of 60.4 min, if compared to a t1/2 = 16.8 min for UniPR129. When orally administered to mice at the same dose, UniPR500 showed an increased systemic exposure, maintaining an in vitro valuable pharmacological profile as an EphA2 receptor antagonist and an overall improvement in its physico-chemical profile (solubility, lipophilicity), if compared to UniPR129. The present work highlights an effective strategy for the pharmacokinetic optimization of aminoacid conjugates of bile acids as small molecule Eph–ephrin antagonists.

A Soft Spot for Chemistry–Current Taxonomic and Evolutionary Implications of Sponge Secondary Metabolite Distribution

Marine sponges are the most prolific marine sources for discovery of novel bioactive compounds. Sponge secondary metabolites are sought-after for their potential in pharmaceutical applications, and in the past, they were also used as taxonomic markers alongside the difficult and homoplasy-prone sponge morphology for species delineation (chemotaxonomy). The understanding of phylogenetic distribution and distinctiveness of metabolites to sponge lineages is pivotal to reveal pathways and evolution of compound production in sponges. This benefits the discovery rate and yield of bioprospecting for novel marine natural products by identifying lineages with high potential of being new sources of valuable sponge compounds. In this review, we summarize the current biochemical data on sponges and compare the metabolite distribution against a sponge phylogeny. We assess compound specificity to lineages, potential convergences, and suitability as diagnostic phylogenetic markers. Our study finds compound distribution corroborating current (molecular) phylogenetic hypotheses, which include yet unaccepted polyphyly of several demosponge orders and families. Likewise, several compounds and compound groups display a high degree of lineage specificity, which suggests homologous biosynthetic pathways among their taxa, which identifies yet unstudied species of this lineage as promising bioprospecting targets.

Introduction

This introductory chapter provides a background of the Philippine Village exhibit at the St. Louis World's Fair in 1904. Despite the supposedly comprehensive nature of the Philippine display, the exhibit was ultimately called upon to serve two sometimes divergent scientific and pedagogical functions. On the one hand, the Philippine Village was a self-contained exhibit, set apart as an inclusive continuum of indigenous types ranging from the “head-hunting,” “dog-eating,” savage Igorots to the highly civilized Philippine Scouts and Constabulary. By viewing these communities in quick successive comparison, onlookers could draw broad lessons from the “demotic” differences in dress, materials, cultural customs, and habits. The Philippine exhibit was also meant to be an interactive display promoting a sense of otherization and cultural affirmation. This book examines a particularly soft spot in the subjective and contested colonial discourse between colonizer and colonized at the Louisiana Purchase Exposition—that of the Philippine Muslims, also known as Moros. The chapter then describes the Moro Village, which was constructed to effectively commodify and exoticize the mundane aspects of Moro life.

Finding a soft spot for vanadium: a P-bound OCP ligand

The first example of a P-bound phosphaethynolato ligand, [OCP]−, to an early 3d transition metal is presented, along with detailed characterization by single crystal X-ray diffraction, SQuID magnetometry, HFEPR spectroscopy, and computational studies.