Tamoxifen analogues

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

Tamoxifen has several adverse effects on the skin, including edema, flushing, rashes, hyperhidrosis, urticaria, alopecia, and hypertrichosis. Radiation recall dermatitis, a severe painful inflammatory skin reaction in sites that have previously been exposed to ionized radiation, can occur in patients taking tamoxifen (59). In one case the tamoxifen was withdrawn and the skin healed spontaneously in 7 weeks (60). Toremifene, a tamoxifen analogue, was well tolerated during 18 months of continuous treatment no signs of radiation recall developed. 

Hardcastle IR, Rowlands MG, Houghton J, Parr IB, Potter GA, Jarman M, Edwards KJ, Laughton CA, Trent JO, Neidle S (1995) Rationally designed analogues of tamoxifen with improved calmodulin antagonism. J Med Chem 38 241-248... 

Rowlands MG, Parr IB, McCague R, Jarman M, Goddard PM (1990) Variation of the inhibition of calmodulin dependent cyclic AMP phosphodiesterase amongst analogues of tamoxifen correlations with cytotoxicity. Biochem Pharmacol 40 283-289... 

Monostory, K., Jemnitz, K., Vereczkey, L. and Czira, G. (1997). Species differences in metabolism of panomifene, an analogue of tamoxifen. Drug Metab. Dispos. 25 1370— 1378. 

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... 

A structural analogue of tamoxifen, toremifene, was also examined. This chemical was found to be less clastogenic than tamoxifen, however positive responses were observed for cells expressing CYP2E1 or CYP3A4 cDNAs and in MCL-5 cells. Studies with synthetic tamoxifen epoxide showed micronuclei induction in all cell lines examined. 

In addition to its limited duration of beneficial effects in breast cancer, a serious problem associated with tamoxifen is its stimulatory effect on the endometrium, leading to endometrial hyperplasia and even cancer (Fisher etal., 1996 Kedar etal., 1994 Robinson etal., 1995). We thus have the example of a compound for which the benefits exerted on breast cancer and bone are accompanied by adverse effects in another tissue. In fact, as mentioned above, even the beneficial effects observed in breast cancer deserve some important comments because of the limit of 5 years of treatment, which raises practical questions about the use of this compound for prevention of breast cancer (Fisher et al., 1996) while, in fact, long-term use is required. Analogues of tamoxifen have... 

A significant difference between the benzothiophenes (raloxifene and analogues) and the triphenylethylenes is the effect on the uterus, namely, whereas tamoxifen and its analogues exert relatively potent stimulatory effects on the uterus, raloxifene and its analogues have weak albeit statistically significant stimulatory effects (Ashby et at., 1997 Bryant, 1996 Sato et at., 1996). 

Top S, Dauer B, Vaissermann J, Jaouen G (1997) Facile route to ferrocifen, 1-[4-(2-dimethy-laminoethoxy)]-l(phenyl-2-ferrocenyl-but-l-ene), first organometallic analogue of tamoxifen, by the McMurry reaction. J Organomet Chem 541 355-361... 

Jarman M, Leung OT, Leclercq G, Devleeschouwer N, Stoessel S, Coombes RC, Skilton RA (1986) Analogues of tamoxifen the role of the basic side-chain. Applications of a whole-cell oestrogen-receptor binding assay to N-oxides and quaternary salts. Anticancer Dmg Des 1 259-268... 

Kraft KS, Ruenitz PC, Bartlett MG (1999) Carboxylic acid analogues of tamoxifen (Z)-2-[p-(l, 2-diphenyl-l-butenyl)phenoxy]-N, N-dimethylethylamine. estrogen receptor affinity and estrogen antagonist effects in MCF-7 cells. J Med Chem 42 3126-3133... 

Nguyen A, Top S, Vessieres A, Pigeon P, Huche M, Hillard EA, Jaouen G (2007) Organo-metallic analogues of tamoxifen effect of the amino side-chain replacement by a carbonyl ferrocenyl moiety in hydroxytamoxifen. J Organomet Chem 692 1219-1225... 

L13. Lucia, M. S., Anzano, M. A., Slayter, M. V., Anver, M. R., Green, D. M., etal., Chemopreventive acitvity of tamoxifen, N-(4-hydroxyphenyl)retamide, and the vitamin D analogue Ro24-5531 for andorgen-promoted carcinomas of the rat seminal vesicle and prostate. Cancer Res. 55, 5621-5627 (1995). 

Other examples of arrays of biologically active compounds accessed through a multi-step RASP approach, include the synthesis of cysteine protease inhibitors by Ellman, and Armstrong s synthesis of a 25-membered array of analogues of the breast cancer drug Tamoxifen. " ... 

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