Identification and Synthesis of Quinolizidines with Anti-Influenza A Virus Activity

Dang, Zhao; Jung, Katherine; Zhu, Li; Wei, Lai; Xie, Hua; Lee, Kuo Hsiung̀; Huang, Li; Chen, Chin Ho

doi:10.1021/ml500236n

Cited by 54 publications

(46 citation statements)

References 20 publications

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“…As a result, several classes of natural products were identified to have anti-IAV activity, including quinolizidine alkyloids. 12 In this study, we found that two diterpenoids, (+)-podocarpic acid (PA) and (+)-totarol, could inhibit IAV at low micromolar concentrations. PA and totarol are both abietane type tricyclic phenolic diterpenoids ( Figure 1) and can be found in resins from the New Zealand conifers Dacrydium cupressinum 13 and Podocarpus totara.…”

Section: Nfluenza Virus Infection Causes a Contagious Respiratorymentioning

confidence: 95%

Phenolic Diterpenoid Derivatives as Anti-Influenza A Virus Agents

Dang

Jung

Zhu

et al. 2015

ACS Med. Chem. Lett.

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A series of diterpenoid derivatives based on podocarpic acid were synthesized and evaluated as anti-influenza A virus agents. Several of the novel podocarpic acid derivatives exhibited nanomolar activities against an H1N1 influenza A virus (A/Puerto Rico/8/34) that was resistant to two anti-influenza drugs, oseltamivir and amantadine. This class of compounds inhibits the influenza virus by targeting the viral hemagglutinin-mediated membrane fusion. These results indicated that podocarpic acid derivatives may serve as potential drug candidates to fight drug-resistant influenza A virus infections.

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Section: Nfluenza Virus Infection Causes a Contagious Respiratorymentioning

confidence: 95%

Phenolic Diterpenoid Derivatives as Anti-Influenza A Virus Agents

Dang

Jung

Zhu

et al. 2015

ACS Med. Chem. Lett.

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“…Aloperine exhibits antiinflammatory, anti-allergic [17,18], and antiviral activity [19]; inhibits proliferation of HCT116 cancer cells; initiates apoptosis; and interrupts the cell cycle [20].…”

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confidence: 99%

New Aloperine–Isoflavone Conjugates

2016

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The reaction of aloperine with isoflavone glycidyl ethers was investigated. A series of alkaloid-isoflavonoid conjugates were synthesized via regioselective opening of the oxirane ring by aloperine.Keywords: aloperine, isoflavone, propanolamine, isoflavone glycidyl ether.E-Adrenoblockers play an important role in the treatment of cardiovascular diseases. Their anti-ischemic, antiarrhythmic, and antihypertensive properties have been used in clinical medicine for many years. Derivatives of phenylpropanolamine and phenoxypropanolamine are typical E-adrenoreceptor blockers [1, 2]. Chromone and flavone derivatives containing a propanolamine fragment are also known to be capable of blocking E-adrenoreceptors [3,4]. Furthermore, several 7-(3-amino-2-hydroxypropoxy) flavonoid derivatives exhibited antihypertensive [5][6][7], antihyperglycemic [8], and antiproliferative [9] activity. Isoflavones containing an aminopropanol fragment showed anti-osteoporosis activity, an estrogen effect [10], and anticancer activity [11].In continuation of research on the synthesis of alkaloid-flavonoid conjugates, it seemed interesting to study the possibility of using a hydroxypropane linker to conjugate 7-hydroxyisoflavones and aloperine, which was isolated as a minor constituent from seeds and leaves of Sophora alopecuroides L. [12][13][14][15][16].Modification of this alkaloid was interesting because of its valuable biological properties. Aloperine exhibits antiinflammatory, anti-allergic [17,18], and antiviral activity [19]; inhibits proliferation of HCT116 cancer cells; initiates apoptosis; and interrupts the cell cycle [20].The phenols for conjugation with aloperine were the natural isoflavones formononetin 1a [21], 2-methylformononetin 1b [22], cladrin 1c [23], afromorsin 1d [24], cladrastin 1e [23], pseudobaptigenin 1f [25], and their derivatives 1g-j.Oxiranes are widely used to synthesize phenoxypropanolamines. Their cyclic system can be opened highly regioselectively by N-nucleophiles. Thus, the most common method for synthesizing phenol glycidyl ethers uses attack of the phenols at the oxirane ring of 1-chloro-2,3-epoxypropane (epichlorohydrin) to give the chlorohydrin ethers followed by dehydrochlorination by base to close the epoxide ring [4,5,26,27].

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“…It initiates apoptosis and halts the cell cycle [15]. It is noteworthy that aloperine also has antiviral activity against influenza A virus (IAV) [16]. The synthesis of aloperine derivatives is just as interesting with respect to chemistry and pharmacology.…”

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confidence: 99%

“…The synthesis of aloperine derivatives is just as interesting with respect to chemistry and pharmacology. Thus, the synthesis of N(1)-alkyl aloperine derivatives that improved the potency against H1N1 influenza A virus by five times was reported [16].The intersection of the biosynthetic pathways for alkaloids and flavonoids in a single plant species results in the formation of metabolites containing both fragments. The clearest examples of this are the anticancer alkaloids tonkinensine A and B, which were isolated from Sophora tonkinensis [17].…”

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confidence: 99%

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Synthesis of Aloperine-Containing Mannich Bases of Isoflavones

2015

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The possibility of using the alkaloid aloperine for aminomethylation of a chromone ring was studied. A series of 8- (aloperin-12-yl)methyl-substituted isoflavone derivatives were synthesized.In continuation of research on the ability of quinolizidine alkaloids to undergo electrophilic substitution on a chromone ring of flavonoids [1-3], we studied the alkaloid aloperine (1) isolated as a minor constituent from seeds and leaves of Sophora alopecuroides L. [4][5][6][7][8] or synthesized by the published methods [9][10][11][12].Aloperine exhibits anti-inflammatory and antiallergic activity [13], which is responsible for its therapeutic effect in treating allergic contact dermatitis and eczema [14]. Furthermore, aloperine is a promising chemotherapy agent with significant antiproliferative activity against HCT116 cancer cells. It initiates apoptosis and halts the cell cycle [15]. It is noteworthy that aloperine also has antiviral activity against influenza A virus (IAV) [16]. The synthesis of aloperine derivatives is just as interesting with respect to chemistry and pharmacology. Thus, the synthesis of N(1)-alkyl aloperine derivatives that improved the potency against H1N1 influenza A virus by five times was reported [16].The intersection of the biosynthetic pathways for alkaloids and flavonoids in a single plant species results in the formation of metabolites containing both fragments. The clearest examples of this are the anticancer alkaloids tonkinensine A and B, which were isolated from Sophora tonkinensis [17].The reaction of aloperine and isoflavone under Mannich reaction conditions was studied in order to synthesize similar compounds containing them. The CH components were natural 7-hydroxyisoflavones 2a-d and their analogs 2e and 2f. An important aspect of our research was to find suitable conditions for carrying out the Mannich reaction because it can occur under both base and acid catalysis. As it turned out, the best results were obtained by carrying out the Mannich reaction using paraformaldehyde in anhydrous EtOH in the presence of catalytic amounts of 4-N,N-dimethylaminopyridine (DMAP).

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Identification and Synthesis of Quinolizidines with Anti-Influenza A Virus Activity

Cited by 54 publications

References 20 publications

Phenolic Diterpenoid Derivatives as Anti-Influenza A Virus Agents

Phenolic Diterpenoid Derivatives as Anti-Influenza A Virus Agents

New Aloperine–Isoflavone Conjugates

Synthesis of Aloperine-Containing Mannich Bases of Isoflavones

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