Benzolactone enamides

Authors: Prof. Dr. med. Peter Altmeyer, Prof. Dr. med. Martina Bacharach-Buhles

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Last updated on: 29.10.2020

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Synonym(s)

Apices A; Lobatamide; Necroxime; Oximidine

Definition
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Benzene lactone enamides are natural substances from various sources that show a very high cytotoxic effect in cell tests. The structure of the benolactone-enamide substance class consists of a salicylic acid unit, a macrolactone and an enamide side chain.

Pharmacodynamics (Effect)
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Regarding the mechanism of action, it is known that the members of this substance group are inhibitors of the vacuolar H+-ATPases (V-ATPases). V-ATPases are proton pumps widely used in eukaryotes (Finbow ME et al. 1997), which are found in the membranes of vacuoles, lysosomes and other components of the endomembrane system. They are arranged to pump protons from the cytoplasm into the organelle or intercellular space. In this way, the pH value within the cell can be regulated. This regulation of the pH value has been associated with resistance to cytostatic drugs. The targeted switching off of the V-ATPase ultimately leads to cell death (Stevens Th et al. 1997; Nelson N et al. 1999). However, further development of this group of substances as cytostatic drugs has so far failed due to the extremely high toxicity of these compounds.

Recently, it was found that the spider-transmitted fungus (Rhizopus microsporus) harbours endofungal bacteria (Burkholderia sp.) which produce the necroxime. So far, several necroxime have been identified, which differ in the side chains on the macrolacton ring. It remains to be seen to what extent necroxime prove to be cytostatic agents.

Note(s)
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Furthermore, substances such as apicularen A (obtained by fermentation from Chondromyces robustus), lobatamide (Aplidium lobatum), oximidine (Pseudomonas sp. Q52002), as well as necroxime, which are formed in symbiosis with the fungal host, belong to the substance group of benzene lactone enamides. Besides their structural similarities, all these substances have high cytotoxic effects.

Literature
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  1. Finbow ME et al (1997) The Vacuolar H+-ATPase: A Universal Proton Pump of Eukaryotes J Biochem 324: 697-712
  2. Nelson N et al (1999) Vacuolar and Plasma Membrane Proton-Adenosinetriphosphatases. Physiol Rev 51: 361-385
  3. Stevens Th et al (1997) Structure, Function and Regulation of the Vacuolar (H+)-ATPaseAnnu Rev Cell Dev Biol 13: 779- 808