3 research outputs found
Simplified Pretubulysin Derivatives and Their Biological Effects on Cancer Cells
Tubulin binding agents are a potent
group of cancer chemotherapeutics.
Most of these substances are naturally derived compounds. A novel
substance class of destabilizing agents is the group of tubulysins.
The tubulysins and their derivative pretubulysin have shown high efficacy
in vitro and in vivo. Due to their complex chemical structures, one
major bottleneck of the tubulysins is their accessibility. Biotechnological
as well as chemical production is challenging, especially on larger
scales. Thus, the synthesis of chemically simplified structures is
needed with retained or improved biological activity. Herein is presented
the biological evaluation of two pretubulysin derivatives [2-desmethylpretubulysin
AU816 (<b>1</b>) and phenylpretubulysin JB337 (<b>2</b>)] in comparison to pretubulysin. Both <b>1</b> and <b>2</b> display a simplification in chemical synthesis. It was shown that
both compounds exhibited potent biological activity against cancer
cells. These simplified compounds inhibited tubulin polymerization
in the nanomolar range. The cytotoxic effects of <b>1</b> and <b>2</b> were in a similar range, when compared with pretubulysin
[IC<sub>50</sub> (nM): pretubulysin: 0.6; <b>1</b>: 10; <b>2</b>: 100]. Furthermore, it was shown that cell cycle arrest
is induced and migration is hampered in MDA-MB-231 breast cancer cells.
In conclusion, <b>1</b> was shown to be about 10-fold more active
than <b>2</b> and as potent as pretubulysin