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Synthesis and biological evaluation of SANT-2 and analogues as inhibitors of the hedgehog signaling pathway.

Abstract：

:Hedgehog (Hh) signaling plays an important role in cell signaling of embryonic development and adult tissue homeostasis. In vertebrates, the hh gene encodes three different unique proteins: sonic hedgehog (Shh), desert hedgehog (Dhh) and indian hedgehog (Ihh). Disruption of the Hh signaling pathway leads to severe disorders in the development of vertebrates whereas aberrant activation of the Hh pathway has been associated with several malignancies including Gorlin syndrome (a disorder predisposing to basal cell carcinoma, medulloblastoma and rhabdomyosarcoma), prostate, pancreatic and breast cancers. In vivo evidence suggests the antagonism of excessive Hh signaling provides a route to unique mechanism-based anti-cancer therapies. Recently the small molecule SANT-2 was identified as a potent antagonist of Hh-signaling pathway. Here, we describe the synthesis, SAR studies as well as biological evaluation of SANT-2 and its analogues. Fifteen SANT-2 derivatives were synthesized and analyzed for their interference with the expression of the Hh target gene Gli1 in a reporter gene assay. By comparison of structure and activity important molecular descriptors for Gli inhibition could be identified. Furthermore we identified derivative TC-132 that was slightly more potent than the parent compound SANT-2. Selected compounds were tested for Hh related teratogenic effects in the small teleost model medaka. Albeit Gli expression has indicated a 16-fold higher Hh-inhibiting activity than observed for the plant alkaloid cyclopamine, none of the tested compounds were able to induce the cyclopamine-specific phenotype in the medaka assay.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Büttner A,Seifert K,Cottin T,Sarli V,Tzagkaroulaki L,Scholz S,Giannis A

doi

10.1016/j.bmc.2009.06.008

subject

Has Abstract

pub_date

2009-07-15 00:00:00

pages

4943-54

issue

14

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(09)00565-3

journal_volume

17

pub_type

杂志文章

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