Buxus alkaloids—XII

Kupchan, S. Morris; Kennedy, Robert M.; Schleigh, William R.; Ohta, Genkichi

doi:10.1016/s0040-4020(01)92557-8

Cited by 42 publications

(15 citation statements)

References 23 publications

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“…Full analysis of its HMBC spectrum established all atom connectivities and the NOESY spectrum allowed assignment of the relative stereochemistry, altogether leading to the unambiguous identification of compound 1 as O -tigloylcyclovirobuxeine-B (Figure 3). The configuration at C-20 was determined as depicted and in accordance with the previous assignment [12,13] ( i.e. , *S) by an NOE-effect between CH 3 -21 and H-12β (red arrow in Figure 4) which would not be possible in the *R configuration, as deduced from molecular models obtained by a conformational search.…”

Section: Resultssupporting

confidence: 75%

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Antiprotozoal Activity of Buxus sempervirens and Activity-Guided Isolation of O-tigloylcyclovirobuxeine-B as the Main Constituent Active against Plasmodium falciparum

et al. 2014

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Part of the thesis of J.B.A. A preliminary account on part of this work has been published in abstract form (Planta Med. 2013, 79, 1129. ‡ This work is cordially dedicated to H. M. Schmidt, Havixbeck, the keeper and co-owner of the Buxus hedge under study, on the occasion of her 50th birthday. Abstract: Buxus sempervirens L. (European Box, Buxaceae) has been used in ethnomedicine to treat malaria. In the course of our screening of plant extracts for antiprotozoal activity, a CH 2 Cl 2 extract from leaves of B. sempervirens showed selective in vitro activity against Plasmodium falciparum (IC 50 = 2.79 vs. 20.2 µg/mL for cytotoxicity against L6 rat cells). Separation of the extract by acid/base extraction into a basic and a neutral non-polar fraction led to a much more active and even more selective fraction with alkaloids while the fraction of non-polar neutral constituents was markedly less active than the crude extract. Thus, the activity of the crude extract could clearly be attributed to alkaloid constituents. Identification of the main triterpene-alkaloids and characterization of * OPEN ACCESSMolecules 2014, 19 6185 the complex pattern of this alkaloid fraction was performed by UHPLC/+ESI-QTOF-MS analyses. ESI-MS/MS target-guided larger scale preparative separation of the alkaloid fraction was performed by 'spiral coil-countercurrent chromatography'. From the most active subfraction, the cycloartane alkaloid O-tigloylcyclovirobuxeine-B was isolated and evaluated for antiplasmodial activity which yielded an IC 50 of 0.455 µg/mL (cytotoxicity against L6 rat cells: IC 50 = 9.38 µg/mL). O-tigloylcyclovirobuxeine-B is thus most significantly responsible for the high potency of the crude extract.

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Section: Resultssupporting

confidence: 75%

“…This alkaloid was first isolated from B. sempervirens and described by Kupchan and coworkers in 1967 [12]. Since the spectroscopic data available in the literature were sparse, the full assignment of its NMR data is reported in Table 2 and Figure 4 shows the main NOESY correlations leading to its conclusive identification.…”

Section: Resultsmentioning

confidence: 99%

Antiprotozoal Activity of Buxus sempervirens and Activity-Guided Isolation of O-tigloylcyclovirobuxeine-B as the Main Constituent Active against Plasmodium falciparum

et al. 2014

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“…For spectroscopic methods see [ 16 , 17 ]. The compound was found identical with cyclovirobuxein B which had previously been described as constituent of B. sempervirens , along with the tiglate 18 [ 19 , 20 ]. The bioassays for antitrypanosomal and antiplasmodial activity were the same as described in [ 1 , 16 , 17 ].…”

Section: Methodssupporting

confidence: 56%

A 3D-QSAR Study on the Antitrypanosomal and Cytotoxic Activities of Steroid Alkaloids by Comparative Molecular Field Analysis

et al. 2018

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As part of our research for new leads against human African trypanosomiasis (HAT), we report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type alkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae), some of which are strong trypanocides against Trypanosoma brucei rhodesiense (Tbr), with low toxicity against mammalian cells. Fully optimized 3D molecular models of seventeen congeneric Holarrhena alkaloids were subjected to a comparative molecular field analysis (CoMFA). CoMFA models were obtained for both, the anti-Tbr and cytotoxic activity data. Model performance was assessed in terms of statistical characteristics (R2, Q2, and P2 for partial least squares (PLS) regression, internal cross-validation (leave-one-out), and external predictions (test set), respectively, as well as the corresponding standard deviation error in prediction (SDEP) and F-values). With R2 = 0.99, Q2 = 0.83 and P2 = 0.79 for anti-Tbr activity and R2 = 0.94, Q2 = 0.64, P2 = 0.59 for cytotoxicity against L6 rat skeletal myoblasts, both models were of good internal and external predictive power. The regression coefficients of the models representing the most prominent steric and electrostatic effects on anti-Tbr and for L6 cytotoxic activity were translated into contour maps and analyzed visually, allowing suggestions for possible modification of the aminosteroids to further increase the antitrypanosomal potency and selectivity. Very interestingly, the 3D-QSAR model established with the Holarrhena alkaloids also applied to the antitrypanosomal activity of two aminocycloartane-type compounds recently isolated by our group from Buxus sempervirens L. (Buxaceae), which indicates that these structurally similar natural products share a common structure–activity relationship (SAR) and, possibly, mechanism of action with the Holarrhena steroids. This 3D-QSAR study has thus resulted in plausible structural explanations of the antitrypanosomal activity and selectivity of aminosteroid- and aminocycloartane-type alkaloids as an interesting new class of trypanocides and may represent a starting point for lead optimization.

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“…The present work reveals a state-of-the-art semi-preparative scale isolation method of O -tigloylcyclovirobuxeine-B ( 1 ), a compound with promising antiplasmodial activity. In comparison to previously described extractions of this natural compound [ 5 , 15 ] we have not used any solid packing material. Thereby we achieved a high recovery and purification of our sample during isolation.…”

Section: Discussionmentioning

confidence: 99%

Target-Guided Isolation of O-tigloylcyclovirobuxeine-B from Buxus sempervirens L. by Centrifugal Partition Chromatography

Szabó

Schmidt

2020

Molecules

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The increasing drug resistance of malaria parasites challenges the treatment of this life-threatening disease. Consequently, the development of innovative and effective antimalarial drugs is inevitable. O-tigloylcyclovirobuxeine-B, a nor-cycloartane alkaloid from Buxussempervirens L., has shown promising and selective in vitro activity in previous studies against Plasmodiumfalciparum (Pf), causative agent of Malaria tropica. For further investigations, it is indispensable to develop an advanced and efficient isolation procedure of this valuable natural product. Accordingly, we used liquid–liquid chromatography including centrifugal partition chromatography (CPC) to obtain the pure alkaloid on a semi-preparative scale. Identification and characterization of the target compound was accomplished by UHPLC/+ESI-QqTOF-MS/MS, 1H NMR and 13C NMR. In conclusion, this work provides a new and efficient method to obtain O-tigloylcyclovirobuxeine-B, a valuable natural product, as a promising antiplasmodial lead structure for the development of innovative and safe medicinal agents.

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Buxus alkaloids—XII

Cited by 42 publications

References 23 publications

Antiprotozoal Activity of Buxus sempervirens and Activity-Guided Isolation of O-tigloylcyclovirobuxeine-B as the Main Constituent Active against Plasmodium falciparum

Antiprotozoal Activity of Buxus sempervirens and Activity-Guided Isolation of O-tigloylcyclovirobuxeine-B as the Main Constituent Active against Plasmodium falciparum

A 3D-QSAR Study on the Antitrypanosomal and Cytotoxic Activities of Steroid Alkaloids by Comparative Molecular Field Analysis

Target-Guided Isolation of O-tigloylcyclovirobuxeine-B from Buxus sempervirens L. by Centrifugal Partition Chromatography

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