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Synthesis of some anthrasteroids as potential anti-tumour agents

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posted on 01.10.2012, 13:25 by Sue S.S. Toh-Lewis
It has recently been discovered that 1, 25-dihydroxyvitamin D3, the active form of vitamin D, in addition to its important role in calcium transport activity in bone, intestine and kidney, it is also found to be capable of suppressing cell proliferation and inducing cell differentiation of certain tumour cells such as malignant melanoma, breast cancer, and myeloid leukemia. The utility of 1,25- dihydroxyvitainin D3 and other vitamin D analogues as drugs in the treatment of these cancers has been restricted in part due to their potent calcemic effects. As a consequence, there has been enhanced interest in the development of structurally modified analogues of vitamin D with high cell differentiating ability and low calcemic effects. Selected hydroxylated anthrasteroids were designed to bind to the vitamin D receptors present in certain cancers, thereby inducing cell differentiation and inhibiting cell proliferation with reduction and/ or even elimination of the potent calcemic effects of vitamin D. Following a proposed scheme, the 1 (10-6) abeo-ergosta-5, 7, 9, 22- tetraen-3-one (6), a key intermediate in the synthesis of the target molecule, was synthesized starting with ergosterol. Acetylation of ergosterol gave the acetate, which was protected with 4-phenyl-l,2,4-triazoline-3,5-dione (PTAD). Rearrangement of the adduct with BF3-ether gave the anthrasteroid-3-acetate. Hydrolysis of the acetate gave the alcohol. Oxidation of the alcohol gave 1 (10-6) abeo-ergosta-5,7,9,22-tetraen-3-one (6). The overall yield obtained over the 5-steps was 50%. After a number of unsuccessful attempts to functionalise at C-2, we were able to prepare 1(10-6) abeo-2-carbomethoxyergosta-5,7,9,22-tetraen-3-one (39), that had allowed access to our target molecules (59). Aromatisation of (39) with pyrrolidone hydrotribromide (PHT) gave the phenolic ester, followed by methylation with methyl iodide gave the methoxy ester in good yield. Reduction with lithium aluminium hydride gave the methoxy alcohol. Oxidation of the alcohol with tetra-n-propylammonium perruthenate (TPAP) gave the aldehyde in good yield. A 2-C extention via a Homer-Wadsworth- S Emmons reaction with triethylphosphonoicetate gave the side chain unsaturated ethoxy ester in moderate yield. Catalytic hydrogenation of the ester with Pd/ C gave the saturated ester in quantitative yield. Lastly, reduction of the saturated ester with lithium aluminium hydride gave 3-[1 (10-6) abeo-3- methoxyergosta-l,3,5,7,9-pentaen-2-yIJ-l-propanol (59), our target molecule in good yield. The target molecule (59) was synthesized over 14- steps with an overall yield of 10%.



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© Sue S.S. Toh-Lewis

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A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.

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