In vertebrates, the Müllerian duct elongates along the Wolffian duct, a mesonephric structure that is required for Müllerian duct formation. Recently, several genes required for initial Müllerian duct formation have been identified. However, the precise mechanism of Müllerian duct elongation remains to be elucidated. In this study, we investigated dynamic morphological changes in the elongating Müllerian duct in rat urogenital ridges in organ culture manipulated by microincision and/or chemical inhibitors. Mechanical division of the developing Müllerian duct showed that epithelial cells of the Müllerian duct actively migrate along the anterior–posterior axis independent of the proliferative expansion of the anterior portion of the duct. We found that the PI3K/AKT signaling pathway is activated in the Müllerian duct epithelium and is required for elongation of the tip of the duct; however, migration of Müllerian duct epithelial cells proximal to the tip remains intact when PI3K/AKT is inactivated. Although much is known about the molecular and cellular mechanisms leading to Müllerian duct regression, the present findings provide a fuller understanding of the mechanisms contributing to Müllerian duct formation and to the general process of early tubulogenesis.
We report the design, synthesis, and biological evaluation of a new series of largazole analogues in which a 4-methylthiazoline moiety was replaced with a triazole and tetrazole ring, respectively. Compound 7 bearing a tetrazole ring was identified to show much better selectivity for HDAC1 over HDAC9 than largazole (10-fold). This work could serve as a foundation for further exploration of selective HDAC inhibitors using a largazole molecular scaffold.KEYWORDS: HDAC inhibitor, peptides, macrocycles, largazole, click chemistry H istone deacetylases (HDACs) are a family of enzymes that catalyze the deacetylation of lysine side chains in chromatin, and thereby, these enzymes are involved in a wide range of biological processes such as cell differentiation, proliferation, angiogenesis, and apoptosis.1−4 Up to now, 18 members of the human HDAC family have been identified, which are divided into four distinct classes on the basis of their size, number of catalytic active sites, subcellular localization, and sequence homology to yeast counterparts. 5−7 Class I HDACs (1−3 and 8), class IIa HDACs (4, 5, 7, and 9), class IIb HDACs (6 and 10), and class IV HDACs (11) 1) 19 and romidepsin (FK228) (Figure 1), 20 have been approved by the U.S. Food and Drug Administration (FDA) for cutaneous T-cell lymphoma (CTCL). In most cases, the reported HDAC inhibitors consist of three distinct structural motifs: the Zn(II) binding moiety, a spacer moiety, and a recognition cap group. It should be noted that the cap region is a key factor in current HDACi design because topological differences are observed in the corresponding "cap" regions of HDAC isozymes.Largazole 3 is a natural macrocyclic depsipeptide reported by Luesch and co-workers in 2008, which show promising HDAC1 inhibitory activity and selectivity. 21 These excellent properties of largazole have attracted significant attention and make it a becoming lead molecule for further structural optimization in pursuit of molecules of higher potency or selectivity. Recently, several research groups have completed total synthesis and structure−activity relationship (SAR) studies of largazole.22−37 Among them, only two groups focused mostly on the alteration or elimination of the methyl group of 4-methylthiazoline moiety. 35,36 On the basis of their results, we envisioned that the 4-methylthiazoline moiety is not essential for the potency of largazole, and modification of it is tolerable. By analyzing molecular modeling of the largazole complex with HDAC1 structure, we revealed that the 4-methylthiazoline residue has hydrophobic interactions with the side chains of Phe 150 of the HDAC1, and these interactions may be crucial for HDAC class/isoform selectivity of largazole (Figure 2). Click chemistry has been widely applied in organic
Objective Given the fact that Mullerian Inhibiting Substance (MIS) causes complex remodeling of the urogenital ridge and regression of the Mullerian ducts during male embryonic development, we examined whether MIS could affect similar cell properties such as migration and invasion that could contribute ultimately to micro-metastasis of cancers arising from Mullerian tissues. MIS receptor expressing cell lines found to be invasive and migratory in vivo are examined in an in vivo assay that is cost effective. Methods We designed in vitro and in vivo experiments to determine if MIS inhibited the movement of cancer lines IGROV-1, HEp3, MDA-MB-231, and HT1080 in cell culture invasion/migration chamber assays and in chick embryo metastasis assays. Results . MIS, at concentrations below those that inhibit cell proliferation, blocked in vitro invasion and in vivo migration of epithelial cancer cells that express the MIS receptor. Conclusions While our laboratory has previously established MIS as an inhibitor of cancer cell proliferation using in vitro assays and in vivo xenografts, we now show that MIS can also inhibit in vivo tumor migration.
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