Chemical Interference of Biological Systems with Natural Products

Chemical compounds isolated from natural sources offer unique opportunities to understand life on a molecular level. In this account, an overview over different natural products investigated in our research group over the last decade is presented. We have shown that protein localization in living cells can be controlled by anguinomycins and derivatives. Furthermore, a truncated analog, SB640, was discovered that retained much of the natural product potency. Detailed studies of the iron chelator anachelin led to the development of a bio-inspired platform for the generation of bioactive interfaces. The discovery of natural products isolated from cyanobacteria such as nostocarboline, aerucyclamides, cyanopetolin 1020 and various microcystins is presented and their molecular mechanisms of action were investigated. The last part describes the synthesis and evaluation of various natural products involved in neuritogenesis and synapse reconstruction such as withanolide A, militarinone, farinosone A and C and torrubiellone C. Their potential with regard to their use in regenerative medicine is discussed

Antibody Recognition of Cancer Cells via Glycan Surface Engineering

Stimulation of the body's immune system toward tumor cells is now well recognized as a promising strategy in cancer therapy. Just behind cell therapy and monoclonal antibodies, small molecule-based strategies are receiving growing attention as alternatives to direct immune response against tumor cells. However, the development of small-molecule approaches to modulate the balance between stimulatory immune factors and suppressive factors in a targeted way remains a challenge. Here, we report the cell surface functionalization of LS174T cancer cells with an abiotic hapten to recruit antibodies to the cell surface. Metabolic glycoengineering followed by covalent reaction with the hapten results in antibody recognition of the target cells. Microscopy and flow cytometry studies provide compelling evidence that metabolic glycoengineering and small molecule stimulators can be combined to direct antibody recognition. Keywords: antibody; bioorganic chemistry; cancer; chemical biology; glycoengineerin

Clinically Approved Antibiotics from 2010 to 2022

This review discusses small molecule antibiotics approved for clinical use in the time frame 2010-2022. This time span saw the approval of four synthetic antibiotics (bedaquiline, pretomanid, delafloxacin, tedizolid), nine natural product derivatives (ceftaroline fosamil, cefiderocol, plazomicin, omadacycline, eravacycline, sarecycline, lefamulin, dalbavancin, oritavancin), and one natural product (fidaxomicin)

Total syntheses of strained polycyclic terpenes

Terpenoids constitute a broad class of natural compounds with tremendous variability in structure and bioactivity, which resulted in a strong interest of the chemical community to this class of natural products over the last 150 years. The presence of strained small rings renders the terpenoid targets interesting for chemical synthesis, due to limited number of available methods and stability issues. In this feature article, a number of recent examples of total syntheses of terpenoids with complex carbon frameworks featuring small rings are discussed. Specific emphasis is given to the new developments in strategical and tactical approaches to construction of such system

Concise Total Synthesis of Peyssonnoside A

Peyssonnoside A is a marine-derived sulfated diterpenoid glucoside with a unique 5/6/3/6 tetracyclic skeleton with a highly substituted cyclopropane ring deeply embedded into the structure. Herein, we report the first total synthesis of this natural product in a concise, efficient, scalable, and highly diastereoselective fashion. The aglucone peyssonnosol was synthesized in 21% overall yield after 15 steps, featuring a Simmons–Smith cyclopropanation and Mukaiyama hydration, fully controlled by the spatial structure of the substrates

Zooxanthellae expelled from bleached corals at 33°C are photosynthetically competent

While a number of factors have been linked to coral bleaching, such as high light, high temperature, low salinity, and UV exposure, the best explanation for recent coral bleaching events are small temperature excursions of 1 to 2°C above summer sea-surface temperatures in the tropics which induce the dinoflagellate symbionts (zooxanthellae) to be expelled from the host. The mechanism that triggers this expulsion of the algal symbionts is not resolved, but has been attributed to damage to the photosynthetic mechanism of the zooxanthellae. In the present investigation we addressed the question of whether such expelled zooxanthellae are indeed impaired irreversibly in their photosynthesis. We employed a Microscopy Pulse Amplitude-Modulated (PAM) fluorometer, by which individual zooxanthellae can be examined to study photosynthesis in zooxanthellae expelled when corals are subjected to a temperature of 33°C. We show that the expelled zooxanthellae from Cyphastrea serailia were largely unaffected in their photosynthesis and could be heated to 37°C before showing temperature-induced photosynthetic impairment. These results suggest strongly that the early events that trigger temperature-induced expulsion of zooxanthellae involve a dysfunction in the interaction of the zooxanthellae and the coral host tissue, and not a dysfunction in the zooxanthellae per se

4-Hydroxy-2-pyridone alkaloids: Structures and synthetic approaches

4-Hydroxy-2-pyridone alkaloids exert diverse biological effects, ranging from antifungal, antibacterial, insecticidal and cytotoxic activity to the induction of neurite outgrowth in different cell assays. For this reason, this class of compounds has attracted much attention in the scientific community, resulting in the elucidation of the biosynthesis of some members which are formed by fungal polyketide synthases via tetramic acids by fungal polyketide synthases as well as different total synthesis approaches. This article will give a summary of the so far known structures, overview the different activities of the compounds and disclose the synthetic attempts since 1982

Nitrocatechols as Tractable Surface Release Systems

Anchor aweigh! The synthesis and evaluation of new nitrochatechols for surface modification and tractable release on TiO2 are reported. The properties of catecholate anchoring and nitrobased photocleavable release were merged to create a new tool for surface immobilization and controlled release of small molecules, which was investigated on caged fluorophores as proof-of-principle

Collective Syntheses of Icetexane Natural Products Based on Biogenetic Hypotheses

A divergent synthesis of 10 icetexane natural products based on a proposed biogenetic cationic ring expansion of a reduced carnosic acid derivative is described. Of these icetexanes, (+)-salvicanol, (−)-cyclocoulterone, (−)-coulterone, (−)-obtusinone D, and (−)-obtusinone E have been synthesized for the first time. In addition, the hypothesis for the non-enzymatic biogenesis of benzo[1,3]dioxole natural products has been experimentally investigated. Additional experimental evidence for the abiotic formation of the methylenedioxy unit is provided, as photolysis of the quinone (+)-komaroviquinone resulted in the formation of the [1,3]dioxole-containing natural product (−)-cyclocoulterone and (+)-komarovispirone

Total Synthesis and Structural Revision of Mangrolide D

The unique 18-membered macrocyclic natural product mangrolide D was prepared in totally synthetic form. Key steps feature an Au-catalyzed glycosylation, aza-Michael addition, and LaLi3tris(binaphthoxide) catalyzed epoxidation. Detailed analysis of the constitution and configuration of the carbohydrate segment and the total synthesis of the revised structure led to structural revision of the originally proposed structure