Studies towards steroidal modulators of the Hedgehog/Gli signalling pathway

The modern age faces a progressive lengthening of life span, which is often associated with the onset of degenerative disorders such as Parkinson’s, Alzheimer’s and cancer. These diseases do not yet have a cure. The Hedgehog/Gli signalling pathway is one of the most promising pathways of cellular communication. Pharmacological modulation of this pathway would provide a remarkable approach for new potential therapeutics in regenerative medicine and cancer. Attention was focussed on coagulin L and withanolide F, two natural steroidal lactones featuring interesting reactive functionalities. The aims of this project were to investigate the chemical modifications of these natural products to prepare novel analogues for a structure-activity relationship study. 3β-Methoxy-pregnenolone is known as able to treat degenerative pathologies of the nervous system which could be implicated in Parkinson’s and Alzheimer’s diseases. The 3β-methoxy group also provides metabolic stability in vivo. Therefore, a library of steroidal analogues decorated differently on the right-hand side has been prepared by organometallic additions of heterocycles to the side-chain of this commercially-available steroid. The 14β-hydroxyl group is rarely found amongst withanolides, and no syntheses of withanolides with the cis-C/D ring rearrangement have been reported to date. Thus, the total synthesis of unnatural withanolide analogues based on the Hajos and Parrish ketone was investigated starting with readily available materials. Coagulin L is the major metabolite extracted at AnalytiCon Discovery from plant material. Hence, its conversion into the more active withanolide F was explored. Further elaboration of the left-hand side to provide additional novel compounds for our library of small molecules was also investigated.