Tamoxifen structure

Figure 31.27. Estrogen Receptor-Tamoxifeu Complex. Tamoxifen binds in the pocket normally occupied by estrogen. However, part of the tamoxifen structure extends from this pocket, and so helix 12 cannot pack in its usual position. Instead, this helix blocks the coactivator-binding site.

Table sugar, sec Sucrose Tagatose, structure of, 975 Talose. configuration of, 982 Tamiflu, molecular model of, 130 Tamoxifen, synthesis of, 744 Till] DNA polymerase, PCR and, 1117 Tartaric acid, stereoisomers of, 305-306... 

Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (1998) The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95 927... 

Fig. 4.4. Structure of tamoxifen molecule showing some substructures (modified from De Medina et al. 2004a)... 

Custodio JB, Almeida LM, Madeira VM (1993) The active metabolite hydroxytamoxifen of the anticancer drug tamoxifen induces structural changes in membranes. Biochim Biophys Acta 1153(2) 308-314... 

De Medina P, Favre G, Poirot M (2004a) Multiple targeting by the antitumor drug tamoxifen a structure-activity study. Curr Med Chem Anti-Cancer Agents 4(6) 491-508... 

Wiseman H, Cannon M, Arnstein HR, Barlow DJ (1992a) The structural mimicry of membrane sterols by tamoxifen evidence from cholesterol coefficients and molecular-modelling for its action as a membrane anti-oxidant and an anti-cancer agent. Biochim Biophys Acta 1138(3) 197-202... 

Wright CD, Garrahan NJ, Stanton M, et al. (1994) Effect of long term Tamoxifen therapy on cancellous bone remodeling and structure in women with breast cancer. J Bone Miner Res 9 153-159... 

Besides cancer, tamoxifen induces benign changes in the endometrial and subendometrial structures, which induce a burden of unnecessary examinations (ultrasound, hysteroscopy, biopsy etc.) and surgery (D Cs, hysterectomies) due to misleading or false positive ultrasonographic reports (Dijkhuizen et al. 1996). Since the absolute incidence of the disease is low... 

Eberling JL, Wu C, Tong-Turnbeaugh R, Jagust WJ (2004) Estrogen- and tamoxifen-associated effects on brain structure and function. Neurol mage 21 364-371... 

Species Differences. Species differences in metabolism are amongst the principal reasons that there are species differences in toxicity. Differences in cytochrome P450 is one of the most common reasons for differences in metabolism. For example, Monostory et al. (1997) recently published a paper comparing the metabolism of panomifene (a tamoxifen analog) in four different species. These data serve to address that the rates of metabolism in the non-human species was most rapid in the dog and slowest in the mouse. Thus, one should not a priori make any assumptions about which species will have the more rapid metabolism. Of the seven metabolites, only one was produced in all four species. Both the rat and the dog produced the two metabolites (M5 and M6) produced by human microsomes. So how does one decide which species best represents humans One needs to consider the chemical structure of the metabolites and the rates at which they are produced. In this particular case, M5 and M6 were relatively minor metabolites in the dog, which produced three other metabolites in larger proportion. The rat produced the same metabolites at a higher proportion, with fewer other metabolites than the dog. Thus, in this particular instance, the rat, rather than the dog, was a better model. Table 18.8 offers a comparison of excretion patterns between three species for a simple inorganic compound. 

Sapino A, Pietribiasi F, Bussolati G, and Marchisio PC [1986] Estrogen- and tamoxifen-induced rearrangement of cytoskeletal and adhesion structures in breast cancer MCF-7 cells. Cancer Res 46 2526-2531... 

Resistance to tamoxifen is a complex phenomenon and there is evidence that relapse under tamoxifen therapy is linked to the estrogenicity of the drug. Both, the great success of tamoxifen and its liabilities have boosted the search for new analogues in the past 25 years with the goal of identifying a compoimd with increased anti-tumour activity and with reduced side effects. A second generation of structurally related triphenyl-ethylenes like... 

Fig. 12 Chemical structures of first and second generation non-steroidal anti-estrogens (tamoxifen and derivatives), and novel third generation SERMs...

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