Cytochalasans are known as inhibitors of actin polymerization and for their cytotoxic and migrastatic activity. In this study, we synthesized a series of cytochalasin derivatives that lack a macrocyclic moiety, a structural element traditionally considered essential for their biological activity. We focused on substituting the macrocycle with simple aryl-containing sidechains, and we have also synthesized compounds with different substitution patterns on the cytochalasin core. The cytochalasin analogues were screened for their migrastatic and cytotoxic activity. Compound 24 which shares the substitution pattern with natural cytochalasins B and D exhibited not only significant in vitro migrastatic activity towards BLM cells but also demonstrated inhibition of actin polymerization, with no cytotoxic effect observed at 50 μM concentration. Our results demonstrate that even compounds lacking the macrocyclic moiety can exhibit biological activities, albeit less pronounced than those of natural cytochalasins. However, our findings emphasize the pivotal role of substituting the core structure in switching between migrastatic activity and cytotoxicity. These findings hold significant promise for further development of easily accessible cytochalasan analogues as novel migrastatic agents.

Department of Biochemistry and Microbiology Faculty of Food and Biochemical Technology University of Chemistry and Technology Prague Technická 5 166 28 Prague The Czech Republic

Department of Cell Biology BIOCEV Faculty of Science Charles University Průmyslová 595 252 50 Vestec Prague West Czech Republic

Department of Organic Chemistry Faculty of Chemical Technology University of Chemistry and Technology Prague Technická 5 166 28 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nám 2 160 00 Prague Czech Republic

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