Structure cristalline et moléculaire du cycladiène (dièneoestrol)

Forniés-Marquina, J.M.; Courseille, C.; Busetta, B.; Hospital, M.

doi:10.1107/s056774087200295x

Cited by 15 publications

(8 citation statements)

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“…Bond lengths and angles within the heterocyclic system (Table 1) agree well with the values reported in the literature (Fornies-Marquina et al, 1974;Molina et al, 1989;Zhang et al, 1996;Chen et al, 2000;Dong et al, 2002). The bond lengths indicate some degree of delocalization around the ring system, with the three C N bonds averaging 1.302 (3) Å and the N-N bonds ranging from 1.375 (2) to 1.404 (3) Å .…”

Section: Commentsupporting

confidence: 88%

3-(2-Ethoxyphenyl)-6-phenyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole

et al. 2005

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Section: Commentsupporting

confidence: 88%

3-(2-Ethoxyphenyl)-6-phenyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole

et al. 2005

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“…Data from X-ray crystallography of DES and DIES derivatives indicate that the orientation of the dienic chain of the DIES derivatives is perpendicular to the phenyl planes [32], whereas it is almost linear with the phenyl planes in DES [33]. Thus, the perpendicular dienic chain of DIES derivatives impedes the appropriate intercalation of DIES, but not DES, into DNA.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: The defining link to natural estrogens

Saeed

Rogan²,

Cavalieri³

2008

Intl Journal of Cancer

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Diethylstilbestrol (DES) is a human carcinogen, based on sufficient epidemiological evidence. DES is mainly metabolized to its catechol, 3 0 -hydroxyDES (3 0 -OH-DES), which can further oxidize to DES-3 0 ,4 0 -quinone (DES-3 0 ,4 0 -Q). Similarly to estradiol-3,4-quinone, the reaction of DES-3 0 ,4 0 -Q with DNA would form the depurinating 3 0 -OH-DES-6 0 -N3Ade and 3 0 -OH-DES-6 0 -N7Gua adducts. To prove this hypothesis, synthesis of DES-3 0 ,4 0 -Q by oxidation of 3 0 -OH-DES with Ag 2 O was tried; this failed due to instantaneous formation of a spiro-quinone. Oxidation of 3 0 -OH-DES by lactoperoxidase or tyrosinase in the presence of DNA led to the formation of 3 0 -OH-DES-6 0 -N3Ade and 3 0 -OH-DES-6 0 -N7Gua adducts. These adducts were tentatively identified by LC-MS/MS as 3 0 -OH-DIES with DNA did not produce any depurinating adducts, due to the dienic chain being perpendicular to the phenyl planes, which impedes the intercalation of DIES into the DNA. Enzymic oxidation of 3 0 -OH-DES suggests that the catechol of DES intercalates into DNA and is then oxidized to its quinone to yield N3Ade and N7Gua adducts. These results suggest that the common denominator of tumor initiation by the synthetic estrogen DES and the natural estrogen estradiol is formation of their catechol quinones, which react with DNA to afford the depurinating N3Ade and N7Gua adducts. ' 2008 Wiley-Liss, Inc.Key words: DES catechol quinone; depurinating DES-DNA adducts; metabolic activation of DES Diethylstilbestrol (DES), a potent synthetic estrogen, was obtained in 1938 and thereafter used to prevent spontaneous abortions and premature deliveries.1 In 1971 an association was found between prenatal exposure to DES and clear cell adenocarcinoma of the vagina and cervix in young women.2 Evidence for a causal relationship between transplacental exposure to DES and clear cell adenocarcinoma is conclusive.3-5 Furthermore, it was later reported that women who took DES during pregnancy had a higher incidence of breast cancer.6,7 More recently, it was found that women exposed to DES prenatally also have a higher incidence of breast cancer after age 40. 8,9 The natural estrogens estradiol (E 2 ) and estrone (E 1 ) are metabolically oxidized to their respective catechols, and the catechols are subsequently oxidized to their quinones, in particular the E 1 (E 2 )-3,4-quinones (Q). We have proposed and demonstrated that reaction of the E 1 (E 2 )-3,4-Q with DNA is the first critical step in the initiation of cancer.10-13 The depurinating adducts 4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-1-N7Gua, as well as the resulting apurinic sites in the DNA, are formed in this reaction. These apurinic sites generate mutations that we think can lead to cancer initiation. 13-15The same mechanism of metabolic activation and reaction with DNA has been demonstrated for the synthetic estrogen hexestrol (HES). 16,17 The catechol quinone of HES has chemical and biochemical properties similar to those of E 1 (E 2 )-3,4-Q; namely, it forms analogous depurinating N3Ade...

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“…Les angles observes entre les plans des cycles ph6nyles restent 6galement en accord avec les r6sultats ant~rieurs. Les cycles en position trans par rapport h la double liaison centrale font entre eux un angle de 59 °, alors que l'on observe 61 ° pour le broparoestrol (Fornies-Marquina, Courseille, Busetta & Hospital, 1972) et un angle variant de 59 h 70 ° pour les formes solvat6es du di&hylstilboestrol (Busetta, Courseille & Hospital, 1973). I1 faut noter cette analogie entre la conformation des cycles en position trans du tamoxi-f6ne et de la mol6cule de di6thylstilboestrol 'dis-sym&rique h cycles crois6s' (Precigoux, 1978) (Fig.…”

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