Conjugating Natural Products (1)

Conjugating Natural Products (1)

Published on 18/04/2023

From evolution to solution - natural products are an infinite source of (bio)active compounds. In this series we present how natural products can be conjugated to empower their inherent potential.

Everyone knows the burning sensation after eating a chili. The reason therefore is 8-methyl-N-vanillyl-6-nonenamide – commonly known as Capsaicin, a chemical irritant and neurotoxin for humans and mammals in general. It interacts with the vanilloid receptor subtype 1, a non-selective cation channel expressed for example in sensory nerve fibers in the tongue. Upon activation of the receptor, cations can pass through the cell membrane, resulting in depolarization of the neuron and signaling to the brain. In addition to Capsaicin, this receptor is also activated by noxious thermal heat. Thus, the spiciness of hot peppers is perceived as burning sensation.

As pharmaceutical agent Capsaicin is used in topical ointments and dermal patches to treat various forms of pain and circulatory disorders.

From a conjugation point of view, Capsaicin bears a single phenol function allowing linker attachment via an initial carbamate. In this example, a double self-immolative sequence leads to fragmentation and release of oxathiolone and dimethylimidazolidinone.

Linker-conjugated Capsaicin undergoes self-immolative fragmentation upon reduction.

Huperzine A is a naturally occurring alkaloid mainly found in the chinese firmoss Huperzia serrata. It acts as highly active, reversible acetylcholinesterase inhibitor, thus preventing the decomposition of the neurotransmitter acetylcholine. Besides, it is reported to improve cognitive function. In China, already in 1994, Huperzine A was approved for the treatment of Alzheimer’s disease and is supposed to improve cognitive function. Conjugating Huperzine A to suitable vectors such as antibodies or nanoparticles might allow to improve its pharmacological effects.

Huperzine A carries a single amino function, which can be directly conjugated to benzyl carbamate decorated with a suitable fragmentation trigger such as Val-Cit or Val-Ala.

Linker-conjugated Huperzine A undergoes self-immolative fragmentation in the presence of Cathepsin B.

Lithocholic acid (LCA) is a bile acid generated from chenodeoxycholid acid by bacteria in the gut. While originally known as detergent to facilitate the digestion and absorption of lipids, LCA is meanwhile reported as weak Vitamin D receptor ligand, as potential anti-aging compound, and in the context of apoptosis during early stages of carcinogenesis.

Lithocholic acid carries a single carboxylic acid function, which makes it ideal for ester formation with p-hydroxybenzyl alcohol, which – for example – can be decorated with a pH sensitive self-immolative silyl ether function.

Linker-conjugated lithocholic acid undergoes self-immolative fragmentation under acidic conditions.

→ For more details on the conjugation of natural products, click here

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