Modification of the basic side chain in tamoxifen: effects on microsomal metabolism and in vitro biological activity.

The effect of reducing the basicity of the side chain in tamoxifen (1) on in vitro microsomal metabolism and biological potency has been investigated. The N-methyl-N-(2,2,2-trifluoroethyl) analogue 10 and its 4-hydroxy derivative 18 have been synthesised. The side chain of 10 was not metabolised detectably by rat liver microsomes but a small amount of 18 was formed; there was no evidence of metabolic switching. The lack of metabolism of 10 is unlikely to reflect steric effects since the N,N-diethyl analogue 9 had a metabolism profile similar to that of tamoxifen, but could reflect the reduction in the basicity of the side chain. Compounds 10 and 18 had relative binding affinities (RBA) to oestrogen receptors in rat uterine cytosol and MCF-7 whole cells approximately 5 times lower than the values for tamoxifen (1) and 4-hydroxytamoxifen (3), respectively. Also 10 was similarly less potent than 1 as an inhibitor of the growth of MCF-7 cells in culture although antioestrogenicity was maintained. There was no evidence for improved cell penetration by 10 relative to 1. Of the N-acyl analogues (15-17) of tamoxifen synthesised, the N-trifluoroacetyl analogue 15 had a very low RBA. The N-acetyl (16) and N-formyl (17) analogues had RBA values comparable to that of 1 in cell cytosol or whole cell systems, but did not inhibit growth of MCF-7 cells. Thus, although metabolism of the side-chain in tamoxifen can be inhibited, reduction of biological potency results.