Figure 20 Tamoxifen analog containing an acid side chain.

effort to explore the effect on antiestrogenic activity (Figure 19). The nature of the basic side chain was also varied, with cyclic (e.g., piperidine) and acyclic (e.g., N,N-dimethyl-) amines being investigated. The compounds were tested as mixtures of E/Z isomers. In general, the compounds where the methylene was inserted between the C-ring and ethylene group displayed the highest activity in MCF-7 cells.

For example, compound 37 (R = ā€” (CH2)4 ā€” ) is a 3.54 mmol L ā€” 1 inhibitor of MCF-7 proliferation which is approximately threefold more potent than tamoxifen in this assay (IC50 = 11.28 mmol Lā€” 1). Other flexible analogs displayed reduced potency, i.e., the introduction of a methylene spacer between the ethylene moiety and the phenyl ring bearing the basic side chain was detrimental to activity, no matter what side chain was used. The compounds were tested in a cytoxicity assay using lactate dehydrogenase as a marker in MCF-7 cells, and were shown to be cytostatic rather than cytotoxic. In general, the flexible analogs were shown to be less cytotoxic than tamoxifen itself.

Although the basic side chain of SERMs is a ubiquitous feature that appears to be critical for conferring tissue selectivity, it has become apparent that the amine functionality can be replaced with a carboxylic acid without losing selective estrogenic activity. Tamoxifen derivatives containing acrylic acid86 and oxyacetic acid87 side chains have been previously identified as selective estrogen receptor ligands. More recently, in an effort to reduce the polarity and ionizability of the molecules, Rubin and co-workers have explored oxybutyric acid tamoxifen derivatives (Figure 20).88 For example, oxybutyric acid (38: RBA = 10.3%, human recombinant ERa), dosed either orally or subcutaneously, suppressed osteocalcin and deoxypyridinoline bone markers to a degree similar to that of E2, but had significantly less uterotrophic activity. However, 38 was assayed as a mixture of E/Z isomers, and it is not clear how each component contributes to the overall profile of the mixture. The synthesis of pure geometrical isomers of tamoxifen analogs continues to generate interest, and a recent report has been published that describes the synthesis of (Z)-4-hydroxytamoxifen and an analog containing an acetic acid side chain.89 Conformationally constrained selective estrogen receptor modulators

One of the key structural features that differentiates tamoxifen (a partial agonist on the uterus) from raloxifene (a uterine antagonist) is the position of the basic side chain, which adopts a nonplanar orientation in the case of raloxifene. Grese and co-workers previously described a novel series of SERMs where the side chain is locked in a similar, nonplanar orientation by a trisubstituted, asymmetric carbon, as depicted by 39 ( ). In an effort to remove the asymmetric center, a series of related phenanthridine derivatives was subsequently investigated.91 Compound 40 (RBA = 24%, MCF-7 cell lysate) had the highest affinity of the compounds examined. The corresponding amide (41) was dramatically less potent (RBA = 1%), which suggests that this region of the binding pocket is

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