- The Cephalostatins. 22. Synthesis of bis-steroidal pyrazine pyrones
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Cephalostatin 1 (1), a remarkably strong cancer cell growth inhibitory trisdecacyclic, bis-steroidal pyrazine isolated from the marine tube worm Cephalodiscus gilchristi, continues to be an important target for practical total syntheses and a model for the discovery of less complex structural modifications with promising antineoplastic activity. In the present study, the cephalostatin E and F rings were greatly simplified by replacement at C-17 with an α-pyrone (in 12), typical of the steroidal bufodienolides, and by a dihydro-γ- pyrone (in 16). The synthesis of pyrazine 12 from 5α- dihydrotestosterone (nine steps, 8% overall yield) provided the first route to a bis-bufadienolide pyrazine. Dihydro-γ-pyrone 16 was synthesized in eight steps from ketone 13. While only insignificant cancer cell growth inhibitory activity was found for pyrones 12 and 16, the results provided further support for the necessity of more closely approximating the natural D-F ring system of cephalostatin 1 in order to obtain potent antineoplastic activity.
- Pettit, George R.,Moser, Bryan R.,Mendonca, Ricardo F.,Knight, John C.,Hogan, Fiona
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- Long-range effect of 17-substituents in 3-oxo steroids on 4,5-double bond hydrogenation
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The long-range effect of substituents in the 17-position on the hydrogenation of double bond of the steroidal Δ4-3-ketones in acetic acid on a platinum catalyst is described in a series of testosterone (1) and epitestosterone (5) esters with carboxylic acids of varying alkyl chain length. The ratio 5α-to 5β-products is affected by the nature of substituents in the position 17.
- Sidova, Romana,Stransky, Karel,Kasal, Alexander,Slavikova, Barbora,Kohout, Ladislav
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- Synthesis of high affinity fluorine-substituted ligands for the androgen receptor. Potential agents for imaging prostatic cancer by positron emission tomography
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We have prepared nine androgens substituted with fluorine at C-16 or C-20 to evaluate their potential, as positron emission tomographic (PET) imaging agents for prostatic cancer when labeled with the positron emitting radionuclide fluorine-18 (t( 1/2 ) = 110 min). These compounds represent members from the following classes of androgens: testosterone (T), 5α- dihydrotestosterone (DHT), 7α-methyl-19-nortestosterone (MNT), mibolerone (Mib), and metribolone (R1881). All of these compounds were prepared by functionalization of suitable androgen precursors, and the synthetic routes were developed to allow the introduction of fluorine by a fluoride ion displacement reaction late in the synthesis, as is required for the preparation of these compounds in fluorine-18 labeled form. We have also prepared four androgens in which the C-3 carbonyl or 17β-hydroxyl groups are replaced by fluorine. Most of the fluorine-substituted androgens show high affinity for the androgen receptor (AR), although fluorine substitution lowers their affinity by a small factor. None of the androgens where fluorine replaces oxygen functions at C-3 or C-17 have substantial affinity for AR. Derivatives of the natural androgens (T and DHT) as well as MNT have little affinity for other steroid hormone receptors (progesterone and mineralocorticoid receptors), whereas the Mib and R1881 derivatives have somewhat greater heterologous binding. With sex steroid binding protein, a human serum binding protein, the pattern of binding affinities is nearly the reverse, with derivatives of Mib, R1881 and MNT having low affinity, and DHT and T, high affinity. From these fluorine-substituted compounds, we can select several whose preparation in fluorine-18 labeled form for further tissue distribution studies is merited.
- Liu,Carlson,Katzenellenbogen
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- Direct Synthesis of α-Amino Nitriles from Sulfonamides via Base-Mediated C-H Cyanation
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Herein, we disclose a transition-metal-free reaction system that enables α-cyanation of sulfonamides through C-H bond cleavage for the preparation of α-amino nitriles, including difficult-to-access all-alkyl α-tertiary scaffolds. More than 50 substrate examples prove a wide functional group tolerance. Additionally, its synthetic practicality is highlighted by gram-scalability and the late-stage modification of natural compounds. Mechanistic experiments suggest that this process involves in situ formation of an imine intermediate via base-promoted elimination of HF.
- Shi, Shasha,Yang, Xianyu,Tang, Man,Hu, Jiefeng,Loh, Teck-Peng
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supporting information
p. 4018 - 4022
(2021/05/26)
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- ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS
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The disclosure relates to anti-cancer compounds which are anti-cancer PARP inhibitors of formula Al, A2, A3 or A4 conjugated by a linker to a steroid, whereby the steroid targets the conjugate to the nucleus, as well as to methods for their preparation and use. (I)
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Page/Page column 147-148
(2021/05/21)
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- Chemical synthesis of 2β-amino-5α-androstane-3α,17β-diol N-derivatives and their antiproliferative effect on HL-60 human leukemia cells
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Even though few steroids are used for the treatment of leukemia, 2β-(4-methylpiperazinyl)-5α-androstane-3α,17β-diol (1) was recently reported for its ability to inhibit the proliferation of human leukemia HL-60 cells. With an efficient procedure that we had developed for the aminolysis of hindered steroidal epoxides, we synthesized a series of 2β-amino-5α-androstane-3α,17β-diol N-derivatives structurally similar to 1. Hence, the opening of 2,3α-epoxy-5α-androstan-17β-diol with primary and secondary amines allowed the synthesis of aminosteroids with diverse length, ramification, and functionalization of the 2β-side chain. Sixty-four steroid derivatives were tested for their capacity to inhibit the proliferation of HL-60 cells; thus obtaining first structure-activity relationship results. Ten aminosteroids with long alkyl chains (7-16 carbons) or bulky groups (diphenyl or adamantyl) have shown antiproliferative activity over 78% at 10 μM and superior to that of the lead compound. The 3,3-diphenylpropylamino, 4-nonylpiperazinyl and octylamino derivatives of 5α-androstane-3α,17β-diol inhibited the HL-60 cell growth with IC50 of 3.1, 4.2 and 6.4 μM, respectively. They were also found to induce the HL-60 cell differentiation.
- Thibeault, Dominic,Roy, Jenny,DeRoy, Patrick,Poirier, Donald
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p. 5062 - 5077
(2008/12/22)
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- Controlling the reactive state through cation binding: Photochemistry of enones within zeolites
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The nature of the lowest triplet state of enones is altered by the cations present within Y zeolites. Alkali metal ions, such as Li+, are predicted to interact with the carbonyl unit of enones in a collinear fashion and significantly lower both the p-type n and π-2 orbitals. Excited state energies, estimated at the CIS(D)/6-31+G* level, show that the lowest triplet is n-π* in character for the enones, but switch to π-π* on coordination with Li+. Observed product distribution within zeolite is consistent with this theoretical prediction.
- Uppili, Sundararajan,Takagi, Shinsuke,Sunoj,Lakshminarasimhan,Chandrasekhar,Ramamurthy
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p. 2079 - 2083
(2007/10/03)
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- Synthesis of α,β-unsaturated ketone from α-iodo ketone using photoirradiation
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Irradiation of α-iodo ketone in hexane under a nitrogen atmosphere with a high-pressure mercury lamp (λ>300nm) at room temperature afforded the corresponding α,β-unsaturated ketones in good yield. This reaction affords a new, clean and convenient synthetic method for the α,β-unsaturated ketone.
- Ji, Shun-Jun,Takahashi, Eiji,Takahashi, T. Tomoyoshi,Horiuchi, C. Akira
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p. 9263 - 9266
(2007/10/03)
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- Formation of 5α steroids by biotranformation involving the 5 α-reductase activity of Penicillium decumbens
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The biotransformation of a series of Δ4-3-ketosteroids by the Penicillium decumbens ATCC 10436 has been investigated. Conversion to the 5α-dihydrosteroid was observed substrates of the androsterone and pregne series: the reaction is tolerant of non-polar substituents (Cl and CH3) at C-4 of the substrate, but does not occur in the presence of a 4-hydroxyl group, or with additional unsaturation at the Δ1 or Δ6 positions. A-nor, B-nor, 3-deoxy-, and 3,5-cycloandrostanes are not reduced, but 6-methylenestestosterone is converted to a 6-methylene-5α-dihydro derivative. Several biotransformations are reported which involve oxidoreductase activity at C-3 and/or C-17, either concomitant or independent of Δ4 reduction: the substrate specificity of the oxidoreductase processes has been examined and defined by the use of 3α-hydroxy, 3β-hydroxy, 3-keto, 17β-keto substituted steroids. In this way, the existence in P. decumbens of 3β-hydroxy-3-keto and 17β-hydroxy-17-keto oxidoreductases has been demonstrated.
- Holland, Herbert L.,Dore, Sophia,Xu, Weili,Brown, Frances M.
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p. 642 - 647
(2007/10/02)
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- THE BIOTRANSFORMATION OF SOME STEROIDS BY CEPHALOSPORIUM APHIDICOLA
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Hydroxylation of 5α-androstane-3-one and 3,6-dione by C. aphidicla takes place at C-17β and, in the case of the latter, at C-5α.The fungus reduces 5α-androstan-17-one and the 3,17-dione to the 17β-alcohols. Key Word Index - Cephalosporium aphidicola; fungus; microbiological hydroxylation; steroids.
- Hanson, James R.,Nasir, Habib
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p. 831 - 834
(2007/10/02)
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- Novel 1,2,3-Thiadiazolyl Sulfines from the Reaction of N-Substituted Hydrazones with Thionyl Chloride
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The reaction of 17β-acetoxy-5α-androstan-3-one (ethoxycarbonyl)hydrazone (5a) with neat SOCl2 at 65 deg C gave (1Z)-17β-acetoxy-5α-androst-2-eno-thiadiazole-1-thione S-oxide (6) in 84percent yield.Under similar conditions the corresponding tosyl- and formylhydrazones afforded 17β-acetoxy-5α-androst-2-enothiadiazole (7) in 84percent and 85percent yields, respectively, while the acetylhydrazone gave a mixture of the two products.A single-crystal X-ray of 6 revealed a close (2.66 Angstroem) sulfine-O thiadiazole-S distance suggestive of a weakly attractive interaction.The ethoxycarbonyl hydrazones of a series of cyclohexanone derivatives were similarly reacted with SOCl2.Those substrates having γ-alkyl substituents afforded 1,2,3-thiadiazolyl sulfines in moderate to good yield.The 3,3,5,5-tetramethyl- and 2,5-methanocyclohexanone derivatives gave only the corresponding 1,2,3-thiadiazoles.When 5a was treated with 2 equiv of SOCl2 at -20 deg C, in addition to 6 and 7, the intermediates 17β-acetoxy-2'-(ethoxycarbonyl)-2',5'α-dihydro-5α-androstanothiadiazole 1'-oxide (22) and 17β-acetoxy-2'-(ethoxycarbonyl)-2'H-5α-androst-1-enothiadiazole (23) were isolated.Based on the above and additional mechanistic studies, a mechanism for the formation of 6 and 7 from 5a is proposed.The general behavior of hydrazones with SOCl2 is rationalized in light of this mechanism.
- Britton, Thomas C.,Lobl, Thomas J.,Chidester, Constance G.
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p. 4773 - 4780
(2007/10/02)
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- Stereochemistry of the Palladium-catalyzed Hydrogenation of 3-Oxo-4-ene Steroids. V. A Kinetic Study in Basic and Acidic Media
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Effects of the β-methyl group at C-10 and some oxygen functions (=O, OH, OAc) at C-11, C-17, and C-20 on the rates of hydrogenation of 3-oxo-4-ene steroids have been studied with palladium catalyst in pyridine or THF/HBr as solvent.In contrast to the hydrogenation in pyridine, the rate in THF/HBr was greatly depressed by the presence of 10β-methyl group.The reactivity of the steroids was enhanced by the oxygen functions, in particular, by 11, 17-dioxo group.The effects of the substituents are discussed from a mechanistic consideration based on the obtained results.
- Nishimura, Shigeo,Momma, Yasuhiro,Kawamura, Hideo,Shiota, Michio
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p. 780 - 783
(2007/10/02)
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- Radical-induced Reduction of α,β-Unsaturated Steroid Ketones with Tributyltin Hydride
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Conjugated steroid ketones are reduced stereoselectively with tributyltin hydride in the presence of azobisisobutyronitrile as radical initiator to give the corresponding saturated ketones in high yields.
- Laurent, Henry,Esperling, Peter,Baude, Guenter
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p. 1996 - 1999
(2007/10/02)
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- NAD(P)H Models XV. Reduction of Δ4-3-ketosteroids via their iminium salts, by 1,4-dihydropyridine derivatives
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Pyrrolidinium salts derived from a series of 17-substituted Δ4-3-ketosteroids are reduced by 1-benzyl-1,4-dihydronicotinamide (BNAH) and 2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine (Hantzsch ester, 1 eq.) to the corresponding isomeric 5α- and 5β-enamines which hydrolyse to the corresponding 3-ketosteroids.In the case of the Hantzsch ester reduction, proton transfer from the oxidized Hantzsch ester to the enamine results in the formation of iminium salts, which are further reduced to the corresponding ammonium salts.Mechanistic, stereochemical and biochemical implications of the reactions are discussed.
- Gase, Ronald A.,Pandit, Upendra K.
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p. 334 - 340
(2007/10/02)
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- Mechanistic studies in the photochemical fries rearrangement of enol esters
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Photolysis of several enol esters produces the corresponding 1,3-Fries products, i.e. the keto forms of the β-diketones, as the sole primary photoproducts. The quantum yields of the rearrangements under a variety of conditions were measured. They decrease when the number of fused aromatic rings in the acyl part of the molecules is increased. The photobehaviour of the 2-anthroyl derivative is exceptional, in being affected both by the exciting wavelength and the solvent. Its irradiation at 254 nm results in a photo-Fries rearrangement (p.f.r.) with a yield twice that in ethanol; irradiation at 366 nm causes only inefficient dimerization. Explanations are forwarded for the general photobehaviour of the enol esters and its relation to the 1,3-p.f.r. of aryl esters and to other photoinduced 1,3-shifts.
- Veierov, Dan,Mazur, Yehuda,Fischer, Ernst
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p. 1659 - 1664
(2007/10/02)
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