Central nervous system early structuring

Based on the novel structure and superior antitumor activity against LI210 leukemia, tyiocrebrine (2) was selected as a drug candidate and successfully proceeded to Phase I clinical trials in the early 1960s. However, the trials were eventually terminated in 1966 due to central nervous system (CNS) toxicity, primarily ataxia and disorientation. Too few patients were treated to establish the efficacy of 2. 

The central nervous system (CNS) of vertebrates is a very complex structure derived from a multistep process involving sequential molecular and morphogenetic events that pattern the epiblast first and the neural plate later. During early gastrulation, the concerted and sequential action of both the anterior visceral endoderm (AVE) and the node and its derivatives (axial mesendoderm, AME, and anterior definitive endoderm, ADE) (Beddington and Robertson, 1999 Bachiller et al., 2000) drives the specification of the anterior neuroectoderm, which subsequently is subdivided in three main territories (forebrain, midbrain, and hindbrain) (Gallera, 1971 Storey et al., 1992 Ruiz i Altaba, 1994 Shimamura and Rubenstein, 1997 Rubenstein and Beachy, 1998). 

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