Synthesis and pharmacological evaluation of 8α-estradiol derivatives

Gonzalez, F. Bermejo; Neef, Günter; Eder, Ulrich; Wiechert, Rudolf; Schillinger, E.; Nishino, Yukeshige

doi:10.1016/0039-128x(82)90031-9

Cited by 34 publications

(8 citation statements)

References 14 publications

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“…39 Various methods for the syntheses of the 2-n-alkylestradiols 2, 23, and 24 have been reported in the literature, including the hydrogenation of the corresponding 2-alkenylestradiols that are available by Wittig reactions of 2-formylestradiol, 30 by palladium-catalyzed cross-couplings of 2-iodoestradiol, 40 by a Claisen rearrangement of estrone allyl ether 41 or by alkylation of ortho-lithiated MOM-protected derivatives of 6. 42 Though all of these methods give good results, we decided to investigate a different approach that appeared amenable to a multigram scale, inspired by the synthesis of 2-ethyl-8R-estradiol described by Gonza ´lez et al 43 Friedel-Crafts acylation of the protected estradiol derivative 11 44 with aluminum chloride and acetyl chloride, propionic anhydride, or butyric anhydride afforded the 2-acylated products 12, 13, and 14 in good yields. These were then demethylated using aluminum chloride and trimethylammonium chloride in DCM to give the desired phenols 15, 16, and 17 (Scheme 1).…”

Section: Chemistrymentioning

confidence: 99%

3,17-Disubstituted 2-Alkylestra-1,3,5(10)-trien-3-ol Derivatives: Synthesis, In Vitro and In Vivo Anticancer Activity

et al. 2007

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Estradiol-3,17-O,O-bis-sulfamates inhibit steroid sulfatase (STS), carbonic anhydrase (CA), and, when substituted at C-2, cancer cell proliferation and angiogenesis. C-2 Substitution and 17-sulfamate replacement of the estradiol-3,17-O,O-bis-sulfamates were explored with efficient and practical syntheses developed. Evaluation against human cancer cell lines revealed the 2-methyl derivative 27 (DU145 GI(50) = 0.38 microM) as the most active novel bis-sulfamate, while 2-ethyl-17-carbamate derivative 52 (GI(50) = 0.22 microM) proved most active of its series (cf. 2-ethylestradiol-3,17-O,O-bis-sulfamate 4 GI(50) = 0.21 microM). Larger C-2 substituents were deleterious to activity. 2-Methoxy-17-carbamate 50 was studied by X-ray crystallography and was surprisingly 13-fold weaker as an STS inhibitor compared to parent bis-sulfamate 3. The potential of 4 as an orally dosed anti-tumor agent is confirmed using breast and prostate cancer xenografts. In the MDA-MB-231 model, dramatic reduction in tumor growth or regression was observed, with effects sustained after cessation of treatment. 3-O-Sulfamoylated 2-alkylestradiol-17-O-carbamates and sulfamates have considerable potential as anticancer agents.

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Section: Chemistrymentioning

confidence: 99%

3,17-Disubstituted 2-Alkylestra-1,3,5(10)-trien-3-ol Derivatives: Synthesis, In Vitro and In Vivo Anticancer Activity

et al. 2007

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“…13 (42); 42 (18); 43 (13); 44 (16); 53 (10); 55 (12); 56 (18); 57 (100); 67 (14); 81 (38); 96 (16); 109 (29); 122 (11); 137 (18); 139 (14); 166 (16); 183 (31); 239 (6) [M] + . Anal (16), 41 (100), 42 (25), 43 (45), 44 (30), 51 (12), 53 (28), 55 (35), 56 (30), 57 (83), 65 (15), 67 (28), 68 (13), 77 (29), 78 (10), 79 (36), 80 (21), 81 (25), 82 (98), 83 (14), 91 (24), 93 (18), 94 (13), 95 (10), 97 (10), 98 (15), 99 (13), 107 (12), 108 (15), 109 (10), 110 (26), 111 (10), 121 (12), 122 (19), 135 (15), 136 (11) tert-Butyl 3-Benzylidene-5-methyl-4-oxopiperidine-1-carboxylate (4jf). Triturated from MTBE.…”

Section: Tert-butyl 3-(cyclohexylmethylene)-4-oxopiperidine-1-carboxy...mentioning

confidence: 99%

“…20 The reaction of intermediate enaminones with Li/Mg C-nucleophiles could be used as an alternative to crotonic condensation (Figure 1, step B). Earlier, this transformation was applied in special cases like steroids, 21 opioids, 22 and ligands, 23 but now it is "neglected" and its scope and scalability are still unclear. 24 Here, we expand the scope of formal α-alkylation of ketones from simple methylation to diverse 1°and 2°alkyl substituent installations.…”

mentioning

confidence: 99%

Toward a Chemical Constructor: A Lego-Like Approach for Formal α-Alkylation of Cyclic Ketones

Frolov,

Chuchvera,

Ostapchuk

et al. 2024

J. Org. Chem.

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A conceptual strategy for a formal α-alkylation of α-methylene ketones was developed. Diverse 1°and 2°alkyl substituents were generated in the α-position of various ketones via synthesis of enaminone (step 1) and treatment with organomagnesium (step 2) with subsequent catalytic hydrogenation (step 3, 1°alkyl) or organocopper reagents (step 4, 2°alkyl). Tolerance toward ester, Boc-protected amine, and α-fluoro-substituted ketone moieties was demonstrated. The suitability of the method for late-stage natural product modification was shown.

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“…Because of their high reactivity with XH 2 -acidic compounds, aminal esters have found widespread application as formylating reagents; especially with CH 2 -acidic ketones such as simple dialkyl ketones, 6-9 aryl alkyl ketones, 6,10-16 heteroaryl alkyl ketones, 17-19 1-alkenyl alkyl ketones, 20 α-dialkylamino ketones, 21 α-glycosyl alkyl ketones, 22 cycloalkanones, 10,11,16,20,23-28 4-piperidinones, 29 and steroidal ketones. 30, 31 If an additional acidic functional group is present (e.g. an NH 2 group), this may also be aminomethylenated by the reagent, 10 in some cases accompanied by ring closure.…”

Section: Willi Kantlehner Universität Stuttgart Stuttgart Germanymentioning

confidence: 99%

t-Butoxybis(dimethylamino)methane

Kantlehner

Bowers

2007

Encyclopedia of Reagents for Organic Synthesis

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1 tert-Butoxybis(dimethylamino)methane 1 CH RO NMe 2 NMe 2 (1; R = t-Bu) (t-BAE) [5815-08-7] C 9 H 22 N 2 O (MW 174.33) InChI = 1/C9H22N2O/c1-9(2,3)12-8(10(4)5)11(6)7/h8H,1-7H3 InChIKey = HXRAMSFGUAOAJR-UHFFFAOYAR (2; R = Me) (MAE) [1186-70-5] C 6 H 16 N 2 O (MW 132.24) InChI = 1/C6H16N2O/c1-7(2)6(9-5)8(3)4/h6H,1-5H3 InChIKey = NCIMAYPZWJQYGN-UHFFFAOYAO (aminal esters reactive as aminomethylenating reagents (formylating reagents) for CH 2 -and NH 2 -acidic compounds. The t-butyl analog is somewhat more reactive than the methyl derivative; bis(dimethylamino)carbene can be generated from both compounds) Alternate Name: Bredereck's reagent. Physical Data: (1) bp 50-52 • C/12 mmHg; n 20 D = 1.4250. (2) bp 128 • C/760 mmHg; 32-33 • C/25 mmHg; n 20 D = 1.4158. Solubility: miscible with nonpolar aprotic waterfree solvents (benzene, toluene, cyclohexane, diethyl ether, etc.); react with protic solvents like water (hydrolysis to DMF) or alcohols (alcoholysis affords DMF acetals). Even common solvents like acetonitrile or acetone which are weakly CH-acidic react with the aminal esters on heating. Form Supplied in: colorless to weak yellow, strong aminesmelling liquids. Analysis of Reagent Purity: the best method is 1 H NMR spectroscopic examination of a neat sample. Handling, Storage, and Precautions: both compounds should be handled in a fume hood, with strict exclusion of atmospheric moisture. They should be stored in tightly sealed containers in a refrigerator under an atmosphere of dry nitrogen or argon.Introduction. Alkoxybis(dimethylamino)methanes can be obtained in good yields from N,N,N ,N -tetraalkylformamidinium salts and alcohol-free alkoxides. 2 The reactions have to be conducted in inert, strictly anhydrous solvents like cyclohexane, hexane, ether, or THF, in which unfortunately both reagents are insoluble. As a consequence it is necessary to use relatively large amounts of the solvent and long reaction times (eq 1). In the patent literature it is claimed that by the use of a mixture of DMF and mesitylene as solvent, the yields can be improved to about 95%. 3 In another method, 4 bis(dimethylamino)acetonitrile is used as the starting compound. Alcohol-free alkoxides suspended in absolute ether substitute the cyano group to give the corresponding aminal ester (eq 2). In contrast to the aforementioned method,

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Synthesis and pharmacological evaluation of 8α-estradiol derivatives

Cited by 34 publications

References 14 publications

3,17-Disubstituted 2-Alkylestra-1,3,5(10)-trien-3-ol Derivatives: Synthesis, In Vitro and In Vivo Anticancer Activity

3,17-Disubstituted 2-Alkylestra-1,3,5(10)-trien-3-ol Derivatives: Synthesis, In Vitro and In Vivo Anticancer Activity

Toward a Chemical Constructor: A Lego-Like Approach for Formal α-Alkylation of Cyclic Ketones

t-Butoxybis(dimethylamino)methane

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