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By using a zebrafish embryo model to guide the chromatographic fractionation of antimitotic secondary metabolites, seven podophyllotoxin-type lignans were isolated from a hydroalcoholic extract obtained from the steam bark of <i>Bursera fagaroides</i>. The compounds were identified as podophyllotoxin (<b>1</b>), &#946;-peltatin-A-methylether (<b>2</b>), 5&#8242;-desmethoxy-&#946;-peltatin-A-methylether (<b>3</b>), desmethoxy-yatein (<b>4</b>), desoxypodophyllotoxin (<b>5</b>), burseranin (<b>6</b>), and acetyl podophyllotoxin (<b>7</b>). The biological effects on mitosis, cell migration, and microtubule cytoskeleton remodeling of lignans <b>1</b>&#8315;<b>7</b> were further evaluated in zebrafish embryos by whole-mount immunolocalization of the mitotic marker phospho-histone H3 and by a tubulin antibody. We found that lignans <b>1</b>, <b>2</b>, <b>4,</b> and <b>7</b> induced mitotic arrest, delayed cell migration, and disrupted the microtubule cytoskeleton in zebrafish embryos. Furthermore, microtubule cytoskeleton destabilization was observed also in PC3 cells, except for <b>7</b>. Therefore, these results demonstrate that the cytotoxic activity of <b>1</b>, <b>2,</b> and <b>4</b> is mediated by their microtubule-destabilizing activity. In general, the in vivo and in vitro models here used displayed equivalent mitotic effects, which allows us to conclude that the zebrafish model can be a fast and cheap in vivo model that can be used to identify antimitotic natural products through bioassay-guided fractionation.