Hippadine

Divergent Total Syntheses of Lycorine Alkaloids via a Sequential C-H Functionalization Strategy.[Pubmed:38546258]

J Org Chem. 2024 Apr 5;89(7):4851-4860.

A Pd-catalyzed one-pot sequential C-H functionalization strategy was utilized to prepare four lycorine alkaloids and one pseudo-lycorine alkaloid from the common intermediate 4. By switching the followed oxidative conditions of air, DMSO/H(2)O/I(2), and DMSO/O(2), based on the Pd(PPh(3))(4)/K(2)CO(3)/toluene catalytic system, three key intermediates 12a, 12b, and 12c with different substitution patterns could be obtained in a well-controlled manner. As a result, four natural products gamma-lycorane, Hippadine, anhydrolycorinone, and anhydrolycorine as well as a pseudo-lycorine alkaloid Delta((4a,10b))-6-oxodihydrolycorine were successfully synthesized within 10 steps through this divergent route.

Neuroprotective Activities of Boophone haemanthoides (Amaryllidaceae) Extract and Its Chemical Constituents.[Pubmed:33212961]

Molecules. 2020 Nov 17;25(22):5376.

Parkinson's disease (PD) is a neurodegenerative condition that progresses as age increases, and some of its major symptoms include tremor and postural and movement-related difficulties. To date, the treatment of PD remains a challenge because available drugs only treat the symptoms of the disease or possess serious side effects. In light of this, new treatment options are needed; hence, this study investigates the neuroprotective effects of an organic Boophone haemanthoides extract (BHE) and its bioactive compounds using an in vitro model of PD involving the toxin 1-methyl-4-phenylpyridinium (MPP(+)) and SH-SY5Y neuroblastoma cells. A total of seven compounds were isolated from BHE, viz distichamine (1), 1alpha,3alpha-diacetylnerbowdine (2), Hippadine (3), stigmast-4-ene-3,6-dione (4), cholest-4-en-3-one (5), tyrosol (6), and 3-hydroxy-1-(4'-hydroxyphenyl)-1-propanone (7). Six compounds (1, 2, 4, 5, 6 and 7) were investigated, and five showed neuroprotection alongside the BHE. This study gives insight into the bioactivity of the non-alkaloidal constituents of Amaryllidaceae, since the isolated compounds and the BHE showed improved cell viability, increased ATP generation in the cells as well as inhibition of MPP(+)-induced apoptosis. Together, these findings support the claim that the Amaryllidaceae plant family could be a potential reserve of bioactive compounds for the discovery of neuroprotective agents.

Pd-Catalyzed C-H Halogenation of Indolines and Tetrahydroquinolines with Removable Directing Group.[Pubmed:32657591]

Org Lett. 2020 Aug 7;22(15):5870-5875.

Pd-catalyzed directing-group-assisted regioselective halogenations to C7 of indolines and C8 of tetrahydroquinolines were achieved in good to excellent yields. The practicality and utility of the developed method have been illustrated by various functional group transformations such as arylation, alkenylation, cyanation, and silylation utilizing the installed synthetic handle. The concise synthesis of primaquine, an antimalarial drug, and formal syntheses of two bioactive natural products, Hippadine and pratosine, have also been demonstrated.

Gigantelline, gigantellinine and gigancrinine, cherylline- and crinine-type alkaloids isolated from Crinum jagus with anti-acetylcholinesterase activity.[Pubmed:32335411]

Phytochemistry. 2020 Jul;175:112390.

Three undescribed Amarylidaceae alkaloids, named gigantelline, gigantellinine and gigancrinine, were isolated from Crinum jagus (syn. = Crinum giganteum) collected in Senegal, together with the already known sanguinine, cherylline, lycorine, crinine, flexinine and the isoquinolinone derivative Hippadine. Gigantelline, gigantellinine and gigancrinine were characterized as 4-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenol, its 7-O-demethyl-5ꞌ-hydroxy-4ꞌ-methoxy derivative and 5,6a,7,7a,8a,9-hexahydro-6,9a-ethano[1,3]dioxolo[4,5-j]oxireno[2,3-b]phenanthridin-9-ol, respectively, by using spectroscopic (1D and 2D (1)H and (13)C NMR and HRESIMS) and chemical methods. Their relative configuration was assigned by NOESY NMR spectra and NMR calculations, while the absolute configuration was assigned using electronic circular dichroism (ECD) experiments and calculations. Sanguinine, cherylline, crinine, flexinine, and the isoquinolinone Hippadine, were isolated for the first time from C. jagus. Cherylline, gigantellinine, crinine, flexinine and sanguinine inhibited the activity of AChE in a dose-dependent manner, and inhibition by sanguinine was remarkably effective (IC(50) = 1.83 +/- 0.01 muM). Cherylline and Hippadine showed weak cytotoxicity at 100 muM.

Alkaloids with Activity against the Zika Virus Vector Aedes aegypti (L.)-Crinsarnine and Sarniensinol, Two New Crinine and Mesembrine Type Alkaloids Isolated from the South African Plant Nerine sarniensis.[Pubmed:27801807]

Molecules. 2016 Oct 27;21(11):1432.

Two new Amaryllidaceae alkaloids, belonging to the mesembrine- and crinine-types, named crinsarnine (1) and sarniensinol (2), were isolated from the dried bulbs of Nerine sarniensis together with bowdensine (3), sarniensine (4), Hippadine (5) and 1-O-acetyl-lycorine (6). Crinsarnine (1) and sarniensinol (2) were characterized using spectroscopic and chiroptical methods as (1S,2S,4aR,10bS)-2,7-dimethoxy-1,2,3,4,4a,6-hexahydro-5,11b-ethano[1,3]dioxolo-[4,5-j]phenanthridin-1-yl acetate and (6-(3aR,4Z,6S,7aS)-6-methoxy-1-methyl-2,3,3a,6,7,7a-hexa-hydro-1H-indol-3a-yl)benzo[d][1,3]dioxol-5-yl)methanol, respectively. Furthermore, the complete spectroscopic characterization of bowdensine (3) is reported for the first time. Compounds 1-6 were evaluated against the Orlando reference strain of Aedes aegypti. None of compounds showed mortality against 1st instar Ae. aegypti larvae at the concentrations tested. In adult topical bioassays, only 1 displayed adulticidal activity with an LD(50) = 2.29 +/- 0.049 mug/mosquito. As regards the structure-activity relationship, the pretazettine and crinine scaffold in 2 and 4 and in 1 and 3 respectively, proved to be important for their activity, while the pyrrole[de]phenanthridine scaffold present in 5 and 6 was important for their reactivity. Among the pretazettine group compounds, opening of the B ring or the presence of a B ring lactone as well as the trans-stereochemistry of the A/B ring junction, appears to be important for activity, while in crinine-type alkaloids, the substituent at C-2 seems to play a role in their activity.

New potently bioactive alkaloids from Crinum erubescens.[Pubmed:27624525]

Bioorg Med Chem. 2016 Nov 1;24(21):5418-5422.

Antimalarial bioassay-guided fractionation of the swamp lily Crinum erubescens led to the isolation of four compounds with potent antiplasmodial activity. Compounds 1 and 2 were determined from their spectroscopic data to be the known pesticidal compound cripowellin A and the known pesticidal and antiproliferative compound cripowellin B. 1D and 2D-NMR techniques were used to determine the identities of 3 and 4 as the new compounds cripowellin C and D. A fifth compound was identified as the known alkaloid Hippadine, which was inactive against Plasmodium falciparum. The antiplasmodial IC(50) values of compounds 1-4 were determined to be 30+/-2, 180+/-20, 26+/-2, and 260+/-20nM, respectively, and their antiproliferative IC(50) values against the A2780 human ovarian cancer cell line were 11.1+/-0.4, 16.4+/-0.1, 25+/-2, and 28+/-1nM.

Effects of hippadine on the blood pressure and heart rate in male spontaneously hypertensive Wistar rats.[Pubmed:25456427]

J Ethnopharmacol. 2014 Dec 2;158 Pt A:123-31.

ETHNOPHARMACOLOGICAL RELEVANCE: Hippadine is an alkaloid isolated from Crinum macowanii. Crinum macowanii is used in South Africa to treat oedema, 'heart disease', rheumatic fever, cancer and skin diseases, and belongs to the plant family Amaryllidaceae, assumed to have originated in the South African region. The aim of this study was to evaluate the effect of Hippadine, an alkaloid extracted from Crinum macowanii, on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive Wistar rats (SHR); and to find out if alpha1 and⧸or beta1 adrenoceptors contribute to its effects. MATERIALS AND METHODS: Hippadine (2.5-12.5mg/kg), adrenaline (0.05-0.20mg/kg), atenolol (0.5-40mg/kg) and prazosin hydrochloride (100-500microg/kg) were infused intravenously, and the BP and HR measured via a pressure transducer connecting the femoral artery and the PowerLab. Adrenaline increased the systolic, diastolic and mean arterial BP, while Hippadine, atenolol and prazosin respectively decreased the systolic, diastolic and mean arterial BP. Increases in HR were observed with both adrenaline and prazosin, while reductions in HR were observed with atenolol and Hippadine. Infusion of adrenaline in rats pre-treated with atenolol (30mg/kg), prazosin (400microg/kg), and Hippadine (10mg/kg) led to similar increases in BP and HR in all groups. All changes in HR or BP were significant (p<0.05) and dose dependent. CONCLUSION: Hippadine decreases the BP and HR in SHR, and these effects may be due to alpha1 and beta1 adrenoceptor inhibition.

Synthesis of pyrrolophenanthridine alkaloids based on C(sp(3))-H and C(sp(2))-H functionalization reactions.[Pubmed:25044314]

Chem Asian J. 2014 Sep;9(9):2628-34.

Assoanine, pratosine, Hippadine, and dehydroanhydrolycorine belong to the pyrrolophenanthridine family of alkaloids, which are isolated from plants of the Amaryllidaceae species. Structurally, these alkaloids are characterized by a tetracyclic skeleton that contains a biaryl moiety and an indole core, and compounds belonging to this class have received considerable interest from researchers in a number of fields because of their biological properties and the challenges associated with their synthesis. Herein, a strategy for the total synthesis of these alkaloids by using C-H activation chemistry is described. The tetracyclic skeleton was constructed in a stepwise manner by C(sp(3))-H functionalization followed by a Catellani reaction, including C(sp(2))-H functionalization. A one-pot reaction involving both C(sp(3))-H and C(sp(2))-H functionalization was also attempted. This newly developed strategy is suitable for the facile preparation of various analogues because it uses simple starting materials and does not require protecting groups.

Simple Synthesis of Amides and Weinreb Amides via Use of PPh(3) or Polymer-Supported PPh(3) and Iodine.[Pubmed:24223494]

European J Org Chem. 2010 May;2010(14):10.1002/ejoc.200901420.

The combination of PPh(3)/I(2) has been shown to be effective for conversion of a range of carboxylic acids to 2 degrees , 3 degrees , and Weinreb amides. Simplification of the procedure was possible with the use of polymer-supported PPh(3)/I(2). Weinreb amides produced via the use of polymer-supported PPh(3) could be filtered through a short silica gel plug and used in further transformations. Thus, use of polymer-supported PPh(3) offers potential applicability to diversity-oriented reactions. Formal total syntheses of apocynin and pratosine, as well as syntheses of anhydrolychorinone and Hippadine, have been achieved via the use of this amide-forming method. An attempt has been made to gain insight into this reaction.

Antibacterial agents from the leaves of Crinum purpurascens herb (Amaryllidaceae).[Pubmed:21503179]

Afr Health Sci. 2009 Dec;9(4):264-9.

BACKGROUND: Typhoid fevers and urogenital infections continue to be serious health problems in developing countries. In our search for therapeutic agents from natural sources with potential for the treatment of typhoid fevers and urogenital infections, extract and compounds were obtained from Crinum purpurascens and tested. METHODS: Two alkaloids (4,5-ethano-9,10-methylenedioxy-7-phenanthridone or Hippadine (1) and 4,5-ethano-9-hydroxy-10-methoxy-7-phenanthridone or pratorimine (2)) and one steroid (a-D-glucopyranoside of sitosterol (3)) were isolated from the CH(2)Cl(2)/MeOH (1:1) leaf extract of Crinum purpurascens and screened for antibacterial activity using both agar diffusion and broth dilution techniques. RESULTS: For the CH(2)Cl(2)/MeOH extract, the MIC values obtained were 3 mg/ml (against P. aeruginosa), 4 mg/ml (against E. coli, K. pneumoniae and S. aureus) and 6 mg/ml (against S. typhi and S. paratyphi B), whereas the MBC values varied between 7 and 12 mg/ml. For compound 1, the MIC values varied between 200 and 250 microg/ml, whereas the MBC value was 300 microg/ml against all the bacteria strains used. Compound 2 did not show any antimicrobial activity against these bacteria strains. For compound 3, the MIC values varied between 250 and 300 microg/ml, whereas the MBC values were 300 microg/ml (against S. typhi and S. paratyphi B) and > 300 microg/ml (against the other bacteria strains). CONCLUSION: These data suggest that C. purpurascens leaf extract contains antibacterial agents which could be used in the treatment of typhoid fevers and urogenital infections.

Comparative study of the Kumada, Negishi, Stille, and Suzuki-Miyaura reactions in the synthesis of the indole alkaloids hippadine and pratosine.[Pubmed:16839172]

J Org Chem. 2006 Jul 21;71(15):5807-10.

The total synthesis of Hippadine by a tandem metalation/cross-coupling/lactamization strategy was investigated starting from either 7-bromoindole or a 6-halogenated methyl piperonate. The Kumada and Negishi cross-coupling reactions failed to provide any of the desired product. However, the Stille and Suzuki reactions furnished Hippadine in low yields starting from the electron-deficient methyl 6-iodo- and 6-bromopiperonate, respectively. Starting from the metalated indole, only the Suzuki reaction occurred, affording Hippadine in 67-74% and pratosine in 62% isolated yield.

Bio-guided isolation of cholinesterase inhibitors from the bulbs of Crinum x powellii.[Pubmed:16317657]

Phytother Res. 2005 Nov;19(11):984-7.

In a search for potential acetylcholinesterase (AChE) inhibitors, the ethanol extract of the bulbs of Crinum x powellii (Amaryllidaceae) was found to demonstrate a marked inhibition of this enzyme. Using a bio-guided isolation strategy, linoleic acid ethyl ester has been identified as the compound responsible for this inhibition. Three other molecules - the alkaloid Hippadine, the glycosylated benzyl alcohol derivative calleryanin and 4'-hydroxy-7-methoxyflavan - were also isolated and characterized for the first time from Crinum x powellii. The structures of these compounds were elucidated by spectrometric methods including EI, D/CI mass spectrometry, (1)H, (13)C and 2D NMR experiments. Linoleic acid was also found to inhibit AChE.

A domino amidation route to indolines and indoles: rapid syntheses of anhydrolycorinone, hippadine, oxoassoanine, and pratosine.[Pubmed:16209533]

Org Lett. 2005 Oct 13;7(21):4777-9.

[reaction: see text] When subjected to palladium-catalyzed amidation conditions, 2-triflyloxy phenethyl carbonates undergo, in addition to the expected aryl cross-coupling, an additional amidation with net displacement of the carbonate. The result is a one-step synthesis of indolines which may be oxidized to indoles. The utility of the procedure is illustrated by the two- or three-step syntheses of anhydrolycorinone, Hippadine, oxoassoanine, and pratosine.

Development of an efficient procedure for indole ring synthesis from 2-ethynylaniline derivatives catalyzed by CuII salts and its application to natural product synthesis.[Pubmed:14961661]

J Org Chem. 2004 Feb 20;69(4):1126-36.

The development of efficient methods for the indole synthesis catalyzed by Cu(II) salts and its applications were investigated. Cu(OAc)(2) has been proved to be the best catalyst for the synthesis of various 1-p-tolylsulfonyl or 1-methylsulfonylindoles, which have both electron-withdrawing and electron-donating groups on the aromatic ring and C2 position of indoles. For the primary aniline derivatives, Cu(OCOCF(3))(2) showed good activities, while Cu(OAc)(2) was a good catalyst for the cyclization of secondary anilines. This methodology could be applied to the sequential cyclization reaction for the compounds which have the electrophilic part in the same molecule. By prior treatment with KH, the sequential cyclization was realized to provide the tricyclic ring systems, but it was limited to five- and six-membered rings for the second cyclization. Finally, formal and total synthesis of Hippadine with the Cu(II)-promoted indole synthesis as the key step was accomplished.

Directed ortho metalation approach to C-7-substituted indoles. Suzuki-Miyaura cross coupling and the synthesis of pyrrolophenanthridone alkaloids.[Pubmed:12762681]

Org Lett. 2003 May 29;5(11):1899-902.

[reaction: see text] Although the indole N-phosphinoyl derivative 4 undergoes n-BuLi deprotonation/electrophile quench to afford C-7-substituted products, its deprotection requires harsh conditions. On the other hand, the N-amide 12, upon sequential or one-pot C-2 metalation, silylation, C-7 metalation, and electrophile treatment, furnishes indoles 7 in good overall yields. In combination with the Suzuki-Miyaura protocol, C-7 aryl (heteroaryl)-substituted indoles 14 and 16 are obtained, including Hippadine and pratosine, members of the pyrrolophenanthridone alkaloid family.