- Synthesis and biological evaluation of isofebrifugine analogues
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Isofebrifugine, as a kind of natural quinazolinone alkaloid with important physiological activities and good pharmacological effects, was isolated from a Chinese medicinal plant, Chang Shan (Dichroa febrifuga). In this paper, the synthesis of a series of novel isofebrifugine analogues was accomplished by employing the N-alkylation of 4(3H)-quinazolinones with benzyl (3aR,7aR)-rel-2-(bromomethyl)hexahydrofuro[3,2-b]pyridine-4(2H)carboxylates and the subsequent N-deprotection. These analogues were characterized by1 H NMR,13 C NMR and HRMS spectra. The MTT assay was used to examine the inhibitory effects of these analogues on the growth of human hepatoma cells (HepG2). The results indicated that some halogenated or hemiketal analogues showed interesting inhibition activity.
- Zhang, Jinjin,Huang, Baohua,Lu, Yujing,Li, Wenbin,Zhuang, Zichong,Ke, Donghua,Zhong, Jingpeng,Zhou, Jinlin,Chen, Qian
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p. 1004 - 1010
(2019/11/22)
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- Synthesis of functionalized 3-hydroxypiperidines
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The synthetic versatility of three chemoenzymatically prepared hydroxypiperidine building blocks has been explored, resulting in a library of enantiopure functionalized piperidines. Key steps involved N-acyliminium ion-mediated CC-bond formation and cross-metathesis reactions, after which full deprotection led to the set of free 3-hydroxypiperidines.
- Wijdeven, Marloes A.,Van Delft, Floris L.,Rutjes, Floris P.J.T.
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experimental part
p. 5623 - 5636
(2010/10/02)
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- BF3·Et2O catalyzed diastereoselective nucleophilic reactions of 3-silyloxypiperidine N,O-acetal with silyl enol ether and application to the asymmetric synthesis of (+)-febrifugine
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The asymmetric BF3·Et2O catalyzed nucleophilic reactions of 3-silyloxypiperidine N,O-acetal 10 with silyl enol ethers derived from ketones are described. (+)-Febrifugine 1, an antimalarial alkaloid, was successfully synthesized based
- Liu, Ru-Cheng,Huang, Wei,Ma, Jing-Yi,Wei, Bang-Guo,Lin, Guo-Qiang
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scheme or table
p. 4046 - 4049
(2009/10/11)
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- A concise enantioselective synthesis of (+)-febrifugine
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A short enantioselective synthesis of (+)-febrifugine, a potent antimalarial alkaloid, has been described based on the regioselective asymmetric dihydroxylation of a 1,4-dienic ester as the key step. The strategy also involves chemoselective [3,3]-sigmatr
- Emmanuvel, Lourdusamy,Kamble, Dayanand A.,Sudalai, Arumugam
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experimental part
p. 84 - 88
(2009/06/06)
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- Metabolites of febrifugine and its synthetic analogue by mouse liver S9 and their antimalarial activity against Plasmodium malaria parasite
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Quinazolinone type alkaloids, febrifugine (1) and isofebrifugine (2), isolated from Dichroa febrifuga roots, show powerful antimalarial activity against Plasmodium falciparum. Unfortunately, their emetic effect and other undesirable side effects have precluded their clinical use for malaria. Because of their antimalarial potency, analogues were searched for, with the goal of preserving the strong antimalarial activity, while dramatically reducing side effects. We expected that compounds useful in drug development would exist in metabolites derived from 1 and Df-1 (3), the condensation product of 1 with acetone, by mouse liver S9. Feb-A and -B (4 and 5) were isolated as the major metabolites of 1. In addition to 4 and 5, feb-C and -D (6 and 7) were also purified from the metabolic mixture of 3. Compounds 4 and 5 were compounds oxidized at C-6 and C-2 of the quinazolinone ring of 1, respectively. Compounds 6 and 7, derived from 3, also bear febrifugine type structures in which the 4″- and 6″-positions of the piperidine ring of 1 were oxidized. In vitro antimalarial and cytotoxic tests using synthetically obtained racemic 4-6 and enantiomerically pure 7 demonstrated that 4 and 6 had antimalarial activity against P. falciparum, of similar potency to that of 1, with high selectivity. The antimalarial activity of 5 and 7, however, was dramatically decreased in the test. The in vitro antimalarial activity of analogues 22 and 43, which are stereoisomers of 4 and 6, was also evaluated, showing that 22 is active. The results suggest that basicity of both the 1- and the 1″-nitrogen atoms of 1 is crucial in conferring powerful antimalarial activity. Racemic 4 and 6 exhibited powerful in vivo antimalarial activity against mouse malaria P. berghei, and especially, no serious side effects were observed with 4. Thus, the metabolite 4 appears to be a promising lead compound for the development of new types of antimalarial drugs.
- Hirai, Shingo,Kikuchi, Haruhisa,Kim, Hye-Sook,Begum, Khurshida,Wataya, Yusuke,Tasaka, Hidehisa,Miyazawa, Yuriko,Yamamoto, Keisuke,Oshima, Yoshiteru
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p. 4351 - 4359
(2007/10/03)
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- Asymmetric synthesis of antimalarial alkaloids (+)-febrifugine and (+)-isofebrifugine
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Diastereoselective α,-amidoalkylation of N,O-acetal, derivated from controlled regio and diastereoselective reduction of (S)-N-(4-methoxybenzyl)-3-silyloxyglutarimide provided two diastereomeric 6-allyl-5-silyloxy-2-piperidinones in 76:24 selectivity. The transformation of the major diastereomer into a known advanced intermediate allowed the synthesis of (+)-febrifugine and (+)-isofebrifugine.
- Huang, Pei-Qiang,Wei, Bang-Guo,Ruan, Yuan-Ping
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p. 1663 - 1667
(2007/10/03)
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- Asymmetric synthesis of (+)-febrifugine and (+)-isofebrifugine using yeast reduction
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The antimalarial agents febrifugine (D-1) and isofebrifugine (D-2) were synthesized from chiral 3-piperidinol (D-4), which was asymmetrically prepared by the yeast reduction of 3-piperidone derivatives (DL-3), with dynamic optical resolution.
- Takeuchi, Yasuo,Azuma, Kumiko,Takakura, Kentaro,Abe, Hitoshi,Kim, Hye-Sook,Wataya, Yusuke,Harayama, Takashi
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p. 1213 - 1218
(2007/10/03)
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- Asymmetric synthesis of febrifugine and isofebrifugine using yeast reduction
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The antimalarial agents febrifugine ((+)-1) and isofebrifugine ((+)-2) were asymmetrically synthesized from chiral piperidin-3-ol ((+)-4), which was prepared by the reductive dynamic optical resolution of the 3-piperidone derivatives ((±)-3) using baker's
- Takeuchi,Azuma,Takakura,Abe,Harayama
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p. 1643 - 1644
(2007/10/03)
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- Synthesis of D/L-febrifugine and D/L-isofebrifugine
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Racemic compounds (1 and 2) of the antimalarial agents febrifugine (D-1) and isofebrifugine (D-2) were synthesized using an unusual Claisen rearrangement of allyl enol ether 6 and the stereoselective reduction of 2- allylpiperid-3-one 8. This method is widely applicable to the synthesis of febirifugine derivatives.
- Takeuchi, Yasuo,Hattori, Mayumi,Abe, Hitoshi,Harayama, Takashi
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p. 1814 - 1818
(2007/10/03)
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- Total synthesis of dl-febrifugine and dl-isofebrifugine
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Racemic compounds (1 and 2) of the antimalarial agents febrifugine (d- l) and isofebrifugine (d-2) were synthesized using an unusual Claisen rearrangement of allyl enol ether (7) and the stereoselective reduction of 2- allyl-3-piperidone (8). This method is widely applicable to the synthesis of derivatives needed to study the structure-activity relationship of febrifugine.
- Takeuchi, Yasuo,Abe, Hitoshi,Harayama, Takashi
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p. 905 - 906
(2007/10/03)
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