Abstract part A: The dysregulation of the Hedgehog (Hh) signaling pathway plays a pivotal role in the generation and cell-manteinance of many human cancers. Gli transcription factors, the final effectors of the pathway, represent the most promising target for the development of new drugs targeting the Hh pathway in tumors. In a previous work, a natural isoflavone, glabrescione B (GlaB) (I), was identified as the first small molecule binding Gli1. It is able to inhibit the transcriptional activity of Gli1, by interfering with its interaction with DNA. In order to perform further studies on the mechanism of action of GlaB (I) we developed a total synthesis, while NMR studies demonstrated the interaction of GlaB with Gli1 Biological studies have demonstrated its ability to interfere with the activity of Gli1 by inhibiting the growth of Gli-dependent-Hh-dependent tumor cells such as medulloblastoma (MB) and basal cell carcinoma (BCC) both in vitro and in allograft mouse models. In addition, our new synthetic route, which encompasses just three steps with an overall yield of 15%, provided an efficient synthetic means to enable the investigation of the role of GlaB ring-B in the interaction Gli1-GlaB. In fact, our synthetic strategy allowed the preparation of several GlaB derivativesin order to elucidate the structure-activity relationships (SARs) and to clarify the molecular mechanism underlying its Hedgehog signalling modulation.