5299-09-2Relevant academic research and scientific papers
Development of a pharmacophore for inhibition of human liver cytochrome P- 450 2D6: Molecular modeling and inhibition studies
Strobl,Von Kruedener,Stockigt,Guengerich,Wolff
, p. 1136 - 1145 (1993)
To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (K(i) = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the K(i) values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of K(i) values ranging between 0.005 and 100 μM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.
Biomimetic synthesis of yohimbine and heteroyohimbine alkaloids from 4,21-dehydrogeissoschizine
Kan-Fan,Husson
, p. 1463 - 1466 (1980)
The first biomimetic synthesis of the yohimbine skeleton (7) from a Corynanthe-type precursor (2) is reported as well as the transformation of the latter into both the 19R and 19S heteroyohimbine series. Reactions were performed on an alumina surface.
A Radical Cascade Enabling Collective Syntheses of Natural Products
Wang, Xiaobei,Xia, Dongliang,Qin, Wenfang,Zhou, Ruijie,Zhou, Xiaohan,Zhou, Qilong,Liu, Wentao,Dai, Xiang,Wang, Huijing,Wang, Shuqing,Tan, Ling,Zhang, Dan,Song, Hao,Liu, Xiao-Yu,Qin, Yong
, p. 803 - 816 (2017/06/13)
Natural products have long been important inspirations for the development of chemical methodologies, theories, and technologies, and ultimately, discoveries of new drugs and materials. Chemical syntheses have traditionally yielded individual or small groups of natural products; however, methodology development allowing the synthesis of a large collection of natural products remains scarce. Here, we report an efficient photocatalytic radical cascade method that enables access to libraries of chiral and multiple-ring-fused tetrahydrocarbolinones. The radical cascade can controllably introduce complexity and functionality into products with excellent chemo-, regio-, and diastereoselectivity. The power of this distinct method has been demonstrated by the efficient syntheses of 33 monoterpenoid indole alkaloids belonging to four families.
19-Epialstonine from Amphicome emodi roots
Dinda, Biswanath,Chandra De, Utpal
, p. 2698 - 2700 (2007/10/03)
A new indole alkaloid, 19-epialstonine has been isolated from the ethyl acetate extract of the roots of Amphicome emodi. The structure of the alkaloid has been established on the basis of spectroscopic (including 2D NMR experiments) and chemical studies.
Unified strategy for synthesis of indole and 2-oxindole alkaloids
Martin, Stephen F.,Benage, Brigitte,Geraci, Leo S.,Hunter, James E.,Mortimore, Michael
, p. 6161 - 6171 (2007/10/02)
A concise and general entry to representative indole alkaloids of the yohimboid, heteroyohimboid, corynantheoid, and 2-oxindole classes has been developed exploiting a strategy that features intramolecular Diels-Alder reactions for the facile construction of the D/E ring subunits of the target alkaloids. The efficacy of the approach is first illustrated by a two-step total synthesis of the yohimboid alkaloid oxogambirtannine (2) from 22. Thus, the Diels-Alder substrate 25, which was prepared by nucleophilic addition of vinyl ketene acetal 24 to the intermediate N-acyliminium salt formed in situ upon reaction of 22 with 23, was heated in the presence of benzoquinone to give a mixture of diastereoisomeric cycloadducts 26 and 27; these adducts underwent spontaneous oxidation to furnish 2. In another application of the strategy, the [4+2] heterocyclization of 34a, which was formed upon nucleophilic addition of 1-[(trimethylsilyl)oxy]butadiene to the N-acyliminium salt generated in situ upon treatment of 22 with crotonyl chloride, afforded a mixture (ca. 9:1) of cycloadducts 35a and 36a. The major adduct 35a was converted to 42a using a general procedure for effecting β-carbomethoxylation of enol ethers to give vinylogous carbonates. Subsequent reduction of 42a to the heteroyohimboid alkaloids (±)-tetrahydroalstonine (3) and (±)-cathenamine (4) was achieved by selective delivery of 2 or 1 equiv of hydride, respectively. When 42a was treated with sodium amide, stereoselective β-elimination ensued to give 49, which was converted by chemoselective hydride reduction into the corynantheoid alkaloid (±)-geissoschizine (5). Facile access to alkaloids of the 2-oxindole family was realized by using a new protocol for achieving stereoselective, oxidative rearrangements of β-carboline Nb lactams into 3,3-disubstituted 2-oxindoles. Thus, exposure of 42a to tert-butyl hypochlorite followed by acid and silver ion induced rearrangement of the intermediate 3-chloroindolenine gave 50, with only traces of the C(7) epimer being detected. Hydride reduction of 50 gave (±)-isopteropodine (6), acid-catalyzed isomerization of which furnished an equilibrium mixture (1:3) of 6 and (±)-pteropodine (51). The stereochemical course of the intramolecular hetero-Diels-Alder reaction of 34a to give 35a and 36a as the only isolable cycloadducts was examined by computational analysis. The geometry of the six-atom transition state was established by semiempirical methods by using the standard closed-shell, restricted Hartree-Fock (RHF) version of the AM1 method. With use of this constrained geometry for the six-membered pericyclic array, the overall conformational energies for the four possible transition states 52-55 were minimized by MM2 calculations (MacroModel). The calculated relative energies of these transition states were in the order 52 53 54 55. Since the cyclization of 34a produced only 35a and 36a in an approximately 9:1 ratio via the respective transition states 52 and 53, these calculations correlated qualitatively with the experimental results.
A New Indole Alkaloid, 14α-Hydroxyrauniticine: Structure Revision and Partial Synthesis
Yamanaka, Etsuji,Maruta, Etsuko,Kasamatsu, Satoe,Aimi, Norio,Sakai, Shin-ichiro,et. al.
, p. 3713 - 3721 (2007/10/02)
Oxidation of the enamine (6) with dibenzoyl peroxide followed by reduction with NaBH4 gave the benzoate (8), which was converted to the cis-hydroxyl compound (9), while hydroboration-oxidation of 6 gave the trans-isomer (11).Treatment of a mixture of the enamines (13 and 14) with dibenzoyl peroxide/NaBH4 gave the benzoates (15 and 16), which were converted to 14α-hydroxy-3-isorauniticine (17) and the acetal (18), respectively.Hydroboration-oxidation of 13 gave 14α-hydroxyrauniticine (2), which was found to be identical with the natural alkaloid whose structure had erroneously been proposed as 14β-hydroxy-3-isorauniticine (4).Keywords-indole alkaloid; 14α-hydroxyrauniticine; structure revision; partial synthesis; Uncaria attenuata; enamine; hydroxylation; hydroboration
INTRODUCTION OF HYDROXYL GROUP AT C-14 OF INDOLE ALKALOIDS: THE PARTIAL SYNTHESIS OF 14α-HYDROXYRAUNITICINE
Yamanaka, Etsuji,Maruta, Etsuko,Kasamatsu, Satoe,Aimi, Norio,Sakai, Shin-ichiro,et al.
, p. 3861 - 3864 (2007/10/02)
Stereoselective hydroxylation at C-1 of the indoloquinolizidine (1) to the hydroxyl derivatives (5 and 6) and the partial synthesis of 14α-hydroxyrauniticine (11) from rauniticine (7) are described.
