Recently, we could show that gonadotropin-releasing hormone (GnRH)-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells in vitro and in vivo. In the present study, we have ascertained receptor binding and effects of GnRH-II antagonists on mitogenic signal transduction and on activation of proapoptotic protein Bax. The GnRH-II antagonists tested showed EC 50 values for GnRH-I receptor binding in the range of 1 to 2 nmol/L. The GnRH-II agonist [D-Lys 6 ]GnRH-II showed an EC 50 value for GnRH-I receptor binding of f1,000 nmol/L. Agonistic activity on GnRH-I receptor function with an EC 50 of 13 nmol/L has been determined for [D-Lys 6 ]GnRH-II. Antagonistic activities with EC 50 values in the range of 1 nmol/L were determined for the GnRH-II antagonists. Treatment of human endometrial, ovarian, and breast cancer cells with GnRH-II antagonists resulted in time-dependent activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH 2 -terminal kinase. In addition, treatment with GnRH-II antagonists induced time-dependent activation of proapoptotic protein Bax. GnRH-II antagonists are not involved in activation of protein kinase B/Akt or extracellular signal-regulated kinase 1/2. The GnRH-II antagonists tested had similar binding affinities to the GnRH-I receptor comparable with that of GnRH-I antagonist Cetrorelix. Referring to the cyclic AMP response element reporter gene activation assay, the GnRH-II agonist ]GnRH-II has to be classified as an agonist at the GnRH-I receptor, whereas the GnRH-II antagonists tested are clear antagonists at the GnRH-I receptor. GnRH-II antagonists induce apoptotic cell death in human endometrial, ovarian, and breast cancer cells via activation of stressinduced mitogen-activated protein kinases p38 and c-Jun NH 2 -terminal kinase followed by activation of proapoptotic protein Bax. [Cancer Res 2009;69(16):6473-81]
Dimethyldioxirane ~~~~~The oxygen transfer to the enamines la-f by dimethyldioxcorresponding a-amino ketone 3c (hydride shift) and the amirane (DMD) in acetone solution leads to the a-amino epoxides ides 4d -f (alkyl shift). The a-[bis(trimethylsilyl)]amino epox2a-f. The stability of the a-amino epoxides 2a-f depends ides 2a, b represent the first observable enamine oxides and only on the type of substitution at the nitrogen atom. Thus, emphasize the value of stabilizing such labile epoxides while the epoxides 2a, b could be characterized spetroscopi-through disilylation of the enamine nitrogen atom. cally, the epoxidation of the enamines 1 c -f resulted in the In a recent publication [11 we have demonstrated that dimethyldioxirane reacts with enamines, which bear an a-hydrogen atom at the C -C double bond, to form amino-substituted 1,Cdioxanes. Unfortunately, the intermediary epoxides could not be detected spectroscopically even at low temperatures. The oxygen transfer by dimethyldioxirane occurred selectively at the double bond independent of the amino group, and the observed 1,4-dioxanes result from dimerization of the labile enamine oxides through the mesomerically stabilized 1,3-dipoles. Alternatively, analogous to epoxides which bear a + M substituent, a-amino epoxides should rearrange by an 1,2-hydride shift to the corresponding carbonyl products [*]. Indeed, such rearrangement is observed in the oxidation of enamines by tripletIn this case, attack of molecular oxygen at the C-C double bond forms, besides C-C cleavage products, also a-amino ketones, which have been postulated to be derived from their intermediary a-amino epoxides. Moreover, the formation of the indolinone in the deoxygenation of an indole dioxetane[61 can be interpreted in terms of the corresponding epoxide as intermediate. To date, no direct experimental evidence for u-amino epoxides has been published. Presumably, the destabilizing effect of the a-amino substituent is responsible and, thus, it is not surprising that recently an a-amino epoxide was reported"', in which the destabilizing effect of the electron-rich amino group was arrested through substitution by an electron-withdrawing group.Since silylation is known to diminish dramatically the basicity and nucleophilicity of amines [loal, it was of interest to assess whether such substitution is sufficient to observe N-silylated a-amino epoxides and, if successful, explore the chemical behavior of such hitherto unknown epoxides. Herein we demonstrate that the novel concept of stabilizing a-amino epoxides through disilylation of the enamine nitrogen atom is indeed an effective tool to observe labile enamine oxides. Furthermore, an effort was made to detect intact Nacylated indole epoxides. Results and DiscussionEpoxidation of the bis(trimethy1sily)-substituted enamines 1 a, b by dimethyldioxirane (DMD) afforded the corresponding a-amino epoxides 2a,b (Scheme l), as manifested by low-temperature NMR spectroscopy. The characteristic 'H chemical shifts at 6 = 2.74 for 2 a (R3 = H) and 2.80 ...
An Efficient Route to GABA-Analogous Amino Acids: Cyclopropanation of N-Silylated Allylamines and EnaminesN-Silylated allylamines 1 are effectively transformed into methyl cyclopropanecarboxylates 2 by methyl diazoacetate under Rh,(OAc), catalysis. Derivatives 2a and 2b are smoothly converted into trans-substituted amino acids 6a and 6b, respectively, and to bicyclic y-lactams 5a and 5b. The pharmacologically interesting y-aminobutyric acid (GABA) analogue trans-6a is now available in few steps. Photochemical and thermal Fe(CO),-induced hydrogen shift converts allylamine derivatives 1 into N-silylated enamines 7. While enamine (E)-7a can be cyclopropanated with methyl diazoacetate under Cu(acac), catalysis to afford the desired cyclopropane derivatives 8a in good yield, the other enamines are rather unreactive towards the carbenoid. Use of an optically active catalyst provides 8a with an ee of 56% (cis) and 20% (trans). Acidinduced ring cleavage of 8a gives the P-formyl ester 10a, and reduction of 8 a followed by desilylation provides the aminocyclopropane 14 in good overall yield, thus demonstrating that cyclopropanes like 8a can serve as useful synthetic intermediates.Ungewohnliche Aminosauren') und daraus synthetisierte Peptide finden viel Interesse, z. B. wegen ihrer Enzym-Inhibitor-Eigenschaften2). Haufig sind Aminosauren (Peptide), die Cyclopropan-Ringe und damit konformativ weitgehend starre Bereiche enthalten, von hoher Aussagekraft bei Struktur-Wirkungs-Unters~chungen~). Auch zahlreiche Verbindungen mit struktureller Verwandtschaft zu y-Aminobuttersaure (GABA) wurden hergestellt und als potentielle inhibitorische Neurotransmitter des zentralen Nervensystems gepriift4). Unser Interesse an bifunktionellen CyclopropanDerivaten 5, veranlal3te uns, N-silylierte Allylamine und Enamine als Carbenophile zu untersuchen. Dabei erschlossen wir einen effektiven Zugang zu verschiedenen, auch biologisch wirksamen Aminocyclopropan-Derivaten. Die Cyclopropanierung von Allylaminen durch Carben-(oid)e ist normalerweise nicht moglich, da sich am nucleophilen Stickstoff-Atom N-Ylide bilden, die eine 2,3-sigmatrope Umlagerung zu Homoallylaminen erfahren *). Derartige Verbindungen wurden bei den Umsetzungen von l a und 1 b nicht gefunden. Die Trimethylsilyl-Gruppen schirmen das Stickstoff-Atom effektiv ab und vermindern zudem durch ihre Akzept~r-Wirkung~) die Nucleophilie dieses Zentrums. Deshalb gelingt die Cyclopropanierung der C = CBindung, die durch den induktiven Effekt der (Me3Si)2N-Gruppe ebenfalls eher desaktiviert sein sollte"). Mit dem sterisch starker gehinderten Prenylamin-Derivat 1 c erzielt man auch bei Anwendung eines grol3eren Uberschusses an Diazoessigsaure-methylester nur eine Ausbeute von 26%. Synthese der GABA-analogen Aminosauren 6 a/bDie Freisetzung der Aminosauren 6a/b erfolgte in Etappen (Schema 1). Zunachst iiberfiihrt man die silylierten Verbindungen 2 a/b durch Einwirkung von trockenem Chlorwasserstoff quantitativ in die Ammonium-Salze 4a/b. Mit 2 N NaOH erhalt man aus 4b ein Gemisch des trans-2-(Am...
The N-silylated methyl 2-aminocyclopropanecarboxylate 1 this structural element have previously not been accessible. can be incorporated into a dipeptide via a CsF-mediated con-After desilylation, the aminomethyl-substituted cycloprodensation reaction with N-tosylated phenylalanine chloride pane or cyclopropene derivatives trans-10, 12, and 13 also 5. Due to its instability the corresponding free p-amino acid provided N-protected dipeptides in good yields. could not be isolated up to now, and peptides containingIn preceding papers we have reported on the syntheses of racemic methyl cyclopropanecarboxylates 1 and 21' 1, and the methyl cyclopropenecarboxylate 3i21 via [2 + 11 cycloadditions of the corresponding a$-unsaturated or P,y-unsaturated N,N-bis(trimethy1silyl)amines.COZMe
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