7,12-Dimethylbenz activation

A stmcturally related series of phenyfiiydrazones resulted ia the selection of compound A-007 [2675-35-6] (DEKK-TEC)(37) for the treatment of hormone-dependent tumors. A-007 is an antiestrogen that, ia contrast to tamoxifen, demonstrated inhibitory activity both ia the presence and absence of estradiol ia ZR-75-1 estrogen-dependent human breast cancer cells, and afforded more protection than tamoxifen ia the 7,12-dimethylbenz[i7]anthracene... 

Research in PAH carcinogenesis has made major advances in the past decade. Most notable has been identification of diol epoxide metabolites as the active forms of benzo[a]pyrene, 7,12-dimethylbenz[tf]anthracene, and other carcinogenic PAH. This finding has stimulated enormous research activity and opened the way to determination of the detailed molecular mechanism of action of this important class of carcinogenic molecules. 

Similarly, the potent activity of 7,12-dimethylbenz[aj-anthracene can be destroyed by the presence of methyl groups on the 2-or 3- positions but the 4-methyl derivative remains active. 

Methods for the synthesis of the biologically active dihydrodiol and diol epoxide metabolites of both carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons are reviewed. Four general synthetic routes to the trans-dihydrodiol precursors of the bay region anti and syn diol epoxide derivatives have been developed. Syntheses of the oxidized metabolites of the following hydrocarbons via these methods are described benzo(a)pyrene, benz(a)anthracene, benzo-(e)pyrene, dibenz(a,h)anthracene, triphenylene, phen-anthrene, anthracene, chrysene, benzo(c)phenanthrene, dibenzo(a,i)pyrene, dibenzo(a,h)pyrene, 7-methyl-benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene, 5-methylchrysene, fluoranthene, benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)-fluoranthene, and dibenzo(a,e)fluoranthene. 

This list includes BP, 7,12-dimethylbenz[a]anthracene, 3-methylchol-anthrene, dibenzo[a,i]pyrene and dibenzo[a,h]pyrene. These PAH can be activated both by one-electron oxidation and/or monooxygenation. There are a few PAH with low IP which are inactive (Table I), such as perylene, or weakly active, such as anthanthrene. This indicates that low IP is a necessary, but not sufficient factor for determining carcinogenic activity by one-electron oxidation. These inactive or weakly active PAH have the highest density of positive charge delocalized over several aromatic carbon atoms in their radical cations, whereas the active PAH with low IP have charge mainly localized on one or a few carbon atoms in their radical cations. 

Trust, K.A., A. Fairbrother, andM.J. Hooper. 1994. Effects of 7,12-dimethylbenz[a]anthracene on immune function and mixed-function oxygenase activity in the European starling. Environ, Toxicol. Chem. 13 821-830. 

The ease of formation of PAH cation-radicals is related to their IP. Above a certain IP, activation by one-electron oxidation becomes unlikely because the removal of one electron by the active forms of P450 or peroxidases is more difficult. A cutoff IP above which one-electron oxidation in not likely to occur was tentatively proposed to be about 7.35 eV (Cavalieri and Rogan 1995). For example, 7,12-dimethylbenz[a]-anthracene has an IP of 7.22 eV and is extremely carcinogenic. Benz[a]anthracene has an IP of 7.54 eV and is very weak in this sense. The active carcinogenicity of dibenz[a,h]anthracene (IP 7.61 eV) is not attributable to the one-electron mechanism. It is worth noting that the one-electron transfer is only one of the operating mechanisms of carcinogenesis. 

Smooth muscle relaxant activity. Tine-ture of the gland, administered to rabbits, was active on the bladder and intestine " . Toxic effect. Gum, administered orally to adults, was active. A case of methemoglobinemia occurred in a 5-week-old male infant, after administration of asafetida preparation to alleviate colic. Treatment was with intravenous methylene blue and the infant recovered . Tumor-promoting activity. Water extract of the dried oleoresin, administered externally to mice at a dose of 200 pL/animal, was active vs 7,12-dimethylbenz[a]anthra-cene and croton oil treatment ". ... 

Toxic effect. Water extract of the dried leaf, administered orally to adults, was inactive " ". Infusion of the dried leaf, administered in drinking water to male rats at a dose of 5%, was inactive "". Tumor-promoting effect. Seed oil, administered in ration to rats at a dose of 3.4% of diet, was active. Rats were given 7,12-dimethylbenz[a]anthracene to induce tumorigenesis "". 

Anti-thyroid activity. Boiled rice taken orally by adults at a dose of 350 g/person was inactive on iodine uptake by the thyroid Anti-tumor activity. Bran, administered intraperitoneally to mice at a dose of 100 mg/kg, was active on Sarcoma 180 (solid). The biological activity has been patented . Fermented grains, in the ration of rats, were active. Miso, a paste made from the seeds of Oryza sativa and G lycine max (soybean), was fed ad libitum. The incidence of cancers in the miso treated rats was 20% less than controls vs 7,12-dimethylbenz-[a]anthracene -induced carcinogenesis ". Water extract of dried seed hull, administered intraperitoneally to mice, was active on Sarcoma 180 (ASC). A glycoprotein fraction has been tested. The biological activity reported has been patented . Anti-ulcer activity. A cerebroside fraction of rice bran, administered intraperitoneally to mice at a dose of 100 mg/kg, was inac-... 

Anticarcinogenic Activity of CLA. Anticarcinogenic activity of synthetically prepared CLA was first tested in the two-stage mouse epidermal carcinogenesis model. In this study, 7 days, 3 days, and 5 min prior to 7,12-dimethylbenz[a]anthracene (DMBA) application, CLA was applied directly on the shaved backs of individual mice at doses of20,20, and 10 mg, respectively (7). Control mice were treated similarly with linoleic acid or acetone. All mice were given TPA to effect tumor promotion. It was found that CLA treated mice developed only about half as many papillomas and exhibited a lower tumor incidence than control mice. 

Benzoyl peroxide was tested for promoting activity in groups of 20 and 15 female SEN mice receiving a single topical application of 20 nmol 7,12-dimethylbenz[rz]anthracene (DMBA) followed by either 0.2 inL of a 100 ing/inL solution of benzoyl peroxide in acetone or acetone alone for 51 weeks. At the termination of the experiment, there were no skin tumours among the 15 control mice, compared with 20/20 in the benzoyl peroxide-treated mice p < 0.01), of which 18/20 were squamous-cell carcinomas. The first tumour developed in week 8. All 20 treated mice showed epidennal hyperplasia (Kurokawa et al., 1984). 

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