A lupeol derivative and other isolates with antiplasmodial activity from the stem root of Rauvolfia mannii Stapf. (Apocynaceae).

Rauvolfia mannii is a plant from western and eastern areas of African continent and is widely used in folk medicine for the treatment of various diseases including malaria. Herein, one previously undescribed acylated triterpene (1), together with five already published natural products (2-6) were removed from its roots. The chemical structures of these compounds were determined by spectroscopic and spectrometric means (NMR, HRESIMS, IR and UV). In addition to the isolated triterpenoids, components 5 and 6 are also newly reported from the genus Rauvolfia. Moreover, some constituents were further tested against the chloroquine-sensitive strain of P. falciparum (3D7). It has been found that 3 and 4 showed a moderate antiplasmodial activity with IC50 values of 46.25 and 39.79 µM respectively.

Secondary metabolites of the leaves of Tricalysia atherura N. Hallé (Rubiaceae) and their potential antiplasmodial activity.

One monoterpene indole alkaloid, atheruramine (1) bearing an ether bridge linking, one hydrobenzoin derivative, tricalydioloside (2) and two ursane-type triterpenes, atherurosides (A and B) (3 and 4) were isolated from the leaves of Tricalysia atherura, together with eight known compounds. The structures of these new compounds were elucidated on the basis of the results of spectroscopic analysis, and the relative configurations of compounds 1-3 were established by NOE difference. Four of the metabolites were screened in vitro against both chloroquine (CQ)-sensitive (3D7) and -resistant (Dd2) strains of Plasmodium falciparum; they were found to exhibit moderate activity against chloroquine-resistant (Dd2) (IC50 64.99-92.29 µg/mL). Meanwhile, crude extract possesses high antiplasmodial activity against both 3D7 and Dd2 strains of P. falciparum (IC50 4.39-7.54 µg/mL) and high selectivity indices values (SI > 10) and was found to be safe.

New acylated triterpenoid saponins from the roots of Acacia polyacantha Willd. (Fabaceae).

In our continuing search of saponins from the plants of Fabaceae family, phytochemical investigation of the roots of Acacia polyacantha, led to the isolation and structural characterization of six undescribed triterpenoid saponins, named polyacosides A-F (1-6). Their structures were established, using extensive analysis by NMR techniques, mainly 1D NMR (1H, 13C, and DEPT) and 2D NMR (COSY, NOESY, HSQC, TOCSY and HMBC) experiments, HRESIMS and by comparison with the literature data, as 3-O-[ß-d-xylopyranosyl-(1 â†’ 4)- [ß-d-galactopyranosyl-(1 â†’ 2)-ß-d-xylopyranosyl-(1 â†’ 2)]-α-l-arabinopyranosyl]-21-O-[Cis-2-methoxycinnamoyl] machaerinic acid (1), 3-O-[ß-d-xylopyranosyl-(1 â†’ 4)- [ß-d-galactopyranosyl-(1 â†’ 2)-ß-d-xylopyranosyl-(1 â†’ 2)]-α-l-arabinopyranosyl]-21-O- [Cis-3,4-dimethoxycinnamoyl] machaerinic acid. (2), 3-O- [ß-d-galactopyranosyl-(1 â†’ 2)-ß-d-xylopyranosyl-(1 â†’ 2)-α-l-arabinopyranosyl]-21-O- [Trans-4-methoxycinnamoyl] machaerinic acid (3), 3-O- [ß-d-glucopyranosyl-(1 â†’ 2)-ß-d-glucopyranosyl] -21-O- [Cis-3,4-dimethoxycinnamoyl] machaerinic acid (4), 3-O- [ß-d-glucopyranosyl-(1 â†’ 2)-ß-d-glucopyranosyl] -21-O- [Cis-2-methoxycinnamoyl] machaerinic acid (5) and 3-O- [ß-d-glucopyranosyl-(1 â†’ 2)-ß-d-glucopyranosyl] -21-O- [Trans-4-methoxycinnamoyl] machaerinic acid (6). Our findings highlight the presence of methoxycinnamoyl group linked to C-21 of the machaerinic acid aglycone moiety as first report of 21-methoxycinnamoyl-machaerinic acid derivative from the plants of Acacia genus (Fabaceae). This represents therefore a valuable contribution to the chemotaxonomy of the Acacia genus of Fabaceae family, which is known to be a rich source of triterpenoid saponins.

A New Triterpenoid Saponin from Albizia zygia Induced Apoptosis by Reduction of Mitochondrial Potential Status in Malignant Melanoma Cells.

In our ongoing research program on the proapoptotic function of saponins, two previously undescribed saponins, named zygiaosides E (1: ) and F (2: ), were isolated from the leaves of Albizia zygia. Their structures were established based on extensive analysis of 1D and 2D NMR data, HR-ESI-MS analysis, and by chemical degradation. The proapoptotic effect of zygiaoside E (1: ) was evaluated on human malignant melanoma (A375), human epidermoid cancer (A431), and normal Homo sapiens skin tissue (TE 353.SK.) cell lines by cytometric analysis. Zygiaoside E (1: ) induced apoptosis of the two human cancer cell lines (A375 and A431) in a dose-dependent manner at 1 µM but did not induce apoptosis in noncancerous skin cells (TE 353.Sk), even when treated with concentrations up to 15 µM. The underlying mechanism of the apoptosis induction activity of zygiaoside E (1: ) on the mitochondrial membrane potential status in A375 cells was further assessed by monitoring the uptake rate of DiOC6, a mitochondrial specific and voltage-dependent fluorescent dye. The number of malignant melanoma cells emitting high fluorescence levels was decreased when cells were treated with 3 or 5 µM of zygiaoside E (1: ) during either 12 or 24 h, thereby revealing a drop of mitochondrial membrane potential in A375 cells upon treatment, which indicated mitochondrial perturbation.

In Vitro and In Silico Potential Inhibitory Effects of New Biflavonoids from Ochna rhizomatosa on HIV-1 Integrase and Plasmodium falciparum.

The aim of this study was to identify bioactive secondary metabolites from Ochna rhizomatosa with potential inhibitory effects against HIV and Plasmodium falciparum. A phytochemical study of O. rhizomatosa root barks resulted in the identification of three new biflavonoids (1-3), along with four known ones (4-7). Compound 7 (Gerontoisoflavone A) was a single flavonoid present in the rootbark of the plant and was used as a reference. Compound 1 (IC50 = 0.047 µM) was the only one with a noteworthy inhibitory effect against HIV-1 integrase in vitro. Chicoric acid (IC50 = 0.006 µM), a pure competitive inhibitor of HIV-1 integrase, was used as control. Compound 2 exhibited the highest antiplasmodial activity (IC50 = 4.60 µM) against the chloroquine-sensitive strain of Plasmodium falciparum NF54. Computational molecular docking revealed that compounds 1 and 2 had the highest binding score (-121.8 and -131.88 Kcal/mol, respectively) in comparison to chicoric acid and Dolutegravir (-116 and -100 Kcal/mol, respectively), towards integrase receptor (PDB:3LPT). As far as Plasmodium-6 cysteine s48/45 domain inhibition is concerned, compounds 1 and 2 showed the highest binding scores in comparison to chloroquine, urging the analysis of these compounds in vivo for disease treatment. These results confirm the potential inhibitory effect of compounds 1 and 2 for HIV and malaria treatment. Therefore, our future investigation to find inhibitors of these receptors in vivo could be an effective strategy for developing new drugs.

New triterpenoid saponin from the stems of Albizia adianthifolia (Schumach.) W.Wight.

As part of our continuing study of apoptosis-inducing saponins from Cameroonian Albizia genus, one new triterpenoid saponin, named adianthifolioside J (1), together with the known gummiferaoside E (2), were isolated from Albizia adianthifolia stems. The structure of the new saponin (1), was established on the basis of extensive analysis of 1 D and 2 D NMR (1H-, 13C-NMR, DEPT, COSY, TOCSY, NOESY, HSQC, HSQC-TOCSY and HMBC) and HRESIMS experiments, and by chemical evidence as 3-O-[ß-D-xylopyranosyl-(1→2)-ß-D-fucopyranosyl-(1→6)-ß-D-glucopyranosyl]-21-O-{(2E,6S)-2-(hydroxymethyl)-6-methyl-6-O-{4-O-[(2E,6S)-2,6-dimethyl-6-O-(ß-D-quinovopyranosyl)octa-2,7-dienoyl]-(ß-D-quinovopyranosyl)octa-2,7-dienoyl]}acacic acid-28-O-ß-D-glucopyranosyl-(1→3)-[5-O-acetyl-α-L-arabinofuranosyl-(1→4)]-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranosyl ester (1). The pro-apoptotic activity of the new isolated saponin 1 was evaluated, using Annexin V-FITC binding assay, on the A431 human epidermoid cancer cell. The result showed that adianthifolioside J (1) displayed weak pro-apoptotic activity.

Antimicrobial and cytotoxic activities of indole alkaloids and other constituents from the stem barks of Rauvolfia caffra Sond (Apocynaceae).

Twenty indole alkaloids, among which two undescribed ones named rauvolfianoids A (1) and B (2), were isolated from the stem barks of Rauvolfia caffra Sond along with eight other compounds from other biosynthetic pathways. The structures were elucidated by analysis of spectroscopic data, including 1 D and 2 D NMR; absolute configurations of 1 and 2 were determined by CD exciton chirality method. Compounds 1 and 2 were evaluated for antimicrobial and anticancer activities against three bacterial strains (Escherichia coli, Shigella sp and Salmonella sp) and CRC-related opportunistic pathogens. 1 showed moderate antibacterial activity against Salmonella sp with the MIC value of 25 µg/ml, while 2 exhibited weak selective activity against all tested pathogens. In addition, these alkaloids were characterized as weak apoptosis inducers in HCT116 human colon carcinoma cell line.

Antibacterial and cytotoxic activities of undescribed cassiaric acid and other constituents from Cassia arereh stem barks.

A new lupane-type triterpene, 2α,3ß-dihydroxylupan-29-oic acid (1), and one new ceramide derivative: (2S*,2'R*,3S*,4R*,5R*,7'E,11E,12'E,20E)-N-[2'-hydroxyoctadeca-6,11-dienoyl]-2-aminohexacosa-11,20-diene-1,3,4,5-tetrol (2) were isolated from the ethyl acetate fraction obtained from the methanol extract of the stem barks of Cassia arereh together with seven known compounds. Their structures were characterized using two-dimensional NMR, mass spectrometry, and compared with reported data. To date, this is the first report of the isolation of a multiple double bonds sphingolipid type (2) from this genus. The ethyl acetate extract and selected isolates were examined for antimicrobial and cytotoxic activities in vitro. Betulinaldehyde (5) has shown to be active against all bacterial strains whereas, cassiaric acid (1) and betulinic acid (6) have demonstrated to be moderately active. In addition, cassiaric acid (1) showed the best cytotoxic result against HeLa and MCF-7 cell lines tested with IC50 75.00 µM, while lupeol (3) and betulinic acid (6) displayed weak cytotoxicity at 100.00 µM.

Triterpenoid saponins and others glycosides from the stem barks of Pancovia turbinata Radlk.

In our continuing search of saponins from the plant of Sapindaceae family, phytochemical investigation of the stem barks of Pancovia turbinata Radlk., led to the isolation and structural characterization of two new triterpenoid saponins, named turbinatosides A-B (1-2), one new farnesyl glycoside, named turbinoside A (3), one new coumarin glucoside, named panturboside A (4), together with a known saponin (5). The structures of the new compounds were established, using extensive analysis of NMR techniques, mainly 1D NMR (1H, 13C, and DEPT) and 2D NMR (COSY, NOESY, HSQC, HSQC-TOCSY and HMBC) experiments, HRESIMS and by comparison with the literature data, as 3-O-ß-d-xylopyranosyl-(1 â†’ 3)-α-l-arabinopyranosyl-(1 â†’ 4)-ß-d-glucopyranosyl-(1 â†’ 3)-α-l-rhamnopyranosyl-(1 â†’ 2)-α-l-arabinopyranosylhederagenin 28-O-ß-d-glucopyranosyl ester (1), 3-O-α-l-arabinopyranosyl-(1 â†’ 4)-ß-d-glucopyranosyl-(1 â†’ 3)-α-l-rhamnopyranosyl-(1 â†’ 2)-α-l-arabinopyranosylhederagenin 28-O-ß-d-xylopyranosyl-(1 â†’ 4)-ß-d-glucopyranosyl ester (2), 1-O-{ß-d-glucopyranosyl-(1 â†’ 3)-α-l-rhamnopyranosyl-(1 â†’ 2)-[α-l-rhamnopyranosyl-(1 â†’ 6)]-ß-d-glucopyranosyl}-(2E,6E)-farnes-1,12-diol (3), and 5-O-ß-d-glucopyranosyl-5,6,7-trihydroxy-8-methoxycoumarin (4), respectively. Our findings highlight the presence of -3Rha-2Ara-3hederagenin oligosaccharidic sequence usually described in saponins from Sapindoideae subfamily of Sapindaceae family, as well as farnesol glycosides, and represent therefore a valuable contribution to the chemotaxonomy of the Sapindoideae subfamily.

Glycosides of polygalacic acid from the stem barks of Piper guineense Schum and Thonn.

In a continuation of our study on constituents of P. guineense now focusing on the search for saponins, phytochemical investigation of the n-BuOH fraction of P. guineense stem bark led to the isolation of three previously undescribed triterpenoid saponins, named guineenosides A─C (1─3). Their structures were established on the basis of extensive analysis of 1D and 2D NMR (1H, 13C NMR, DEPT, COSY, TOCSY, NOESY, HSQC, HSQC-TOCSY and HMBC) and HRESIMS experiments, and by chemical evidence as 3-O-{α-l-rhamnopyranosyl-(1 â†’ 3)-ß-d-xylopyranosyl-(1 â†’ 2)-α-l-arabinopyranosyl-(1 â†’ 4)-α-l-rhamnopyranosyl-(1 â†’ 3)-[α-l-arabinofuranosyl-(1 â†’ 4)]-α-l-rhamnopyranosyl-(1 â†’ 3)-ß-d-fucopyranosyl} polygalacic acid 28-O-α-l-rhamnopyranosyl-(1 â†’ 4)-α-l-rhamnopyranosyl-(1 â†’ 3)-ß-d-xylopyranosyl ester (1), 3-O-{α-l-rhamnopyranosyl-(1 â†’ 3)-ß-d-xylopyranosyl-(1 â†’ 2)-α-l-arabinopyranosyl-(1 â†’ 4)-α-l-rhamnopyranosyl-(1 â†’ 3)-[α-l-arabinofuranosyl-(1 â†’ 4)]-α-l-rhamnopyranosyl-(1 â†’ 3)-ß-d-fucopyranosyl} polygalacic acid 28-O-ß-d-glucopyranosyl-(1 â†’ 3)-α-l-rhamnopyranosyl-(1 â†’ 4)-α-l-rhamnopyranosyl-(1 â†’ 3)-ß-d-xylopyranosyl ester (2), and 3-O-{α-l-rhamnopyranosyl-(1 â†’ 2)-ß-d-xylopyranosyl-(1 â†’ 3)-ß-d-fucopyranosyl} polygalacic acid 28-O-[α-l-rhamnopyranosyl-(1 â†’ 4)-α-l-rhamnopyranosyl-(1 â†’ 3)-ß-d-xylopyranosyl ester (3). This is the first report of triterpenoid saponins from P. guineense.

Antiplasmodial activities of indole alkaloids from Tabernaemontana penduliflora K. Schum (Apocynaceae).

Five undescribed carboxy-indole alkaloids with corynanthe skeleton, penduflorines A-E (1-3) as well as a voacangine-N-oxide alkaloid, tabernaemontine (4), were isolated along with eight other known compounds (5-12) from the trunk bark of Tabernaemontana penduliflora K. Schum (Apocynaceae). Their structures were determined by means of spectroscopic and spectrometric methods such as UV, IR, NMR and HR-ESI-MS. Antiplasmodial activities of new isolates were evaluated against two strains of Plasmodium falciparum 3D7 and Dd2 by the Sybr green I-based fluorescence assay setup. Those compounds showed good in vitro activities. Among them, penduflorines A and B (1a and 1b) as well as tabernaemontine (4) showed significant inhibitory activities against the two strains with IC50 values ranged between 1.85 and 7.88 µg/mL. This is the first report of quaternary-N-indole alkaloids (1a, 1b, 2, 3a, 3b and 4) occurring in the form of zwitterion from Tabernaemontana genus.

Experimental and computational studies of an antiplasmodial derivative of allantoin; antimycobacterial essential oil from Cordia batesii WERNHAM (Boraginaceae).

BACKGROUND: Chemical and pharmacological investigations were performed on the stems of Cordia batesii (Boraginaeae); chemical studies included quantum calculations applied on a newly described compound. RESULTS: A new derivative of allantoin (1) named batesiin (2) was characterized. Thirteen other known compounds involving allantoin (1) were either isolated or identified. GC-MS enabled the identification of six compounds from a fraction containing essential oil. MeOH extract and some isolated compounds were tested in vitro against Pf7G8 CQS and Pf Dd2 CQR strains of Plasmodium falciparum; extract disclosed a moderate antiplasmodial activity (IC50 = 50 µg mL-1). Meantime, the CH2Cl2 extract and essential oil fraction were tested on a resistant mycobacterial strain of Mycobacterium tuberculosis; a potent antimycobacterial activity with a MIC = 9.52 µg mL-1 was deduced from essential oil. Density functional theory (DFT) calculations were carried on batesiin (2). Calculated chemical shifts at B3LYP/6-31G(d,p) and MPW1PW91/6-31G+(d,p) showed much better correlations with the experimental data. Time dependent DFT at B3LYP/6-31G+(d,p) displayed a major absorption band 3.01 nm higher than the experimental value. CONCLUSION: Cordia batesii can be considered as promising in search of compounds with antimalarial and antitubercular properties. DFT studies are very helpful when trying to learn more about the spectroscopic insights of a derivative of allantoin (1).

Antiplasmodial and antileishmanial inhibitory activity of triterpenes and steroidal alkaloid from the leaves of Funtumia elastica (Preuss) Stapf (Apocynaceae).

The phytochemical study of leaves of Funtumia elastica led to the isolation of three undescribed ursane derivatives, funtumic acids A, B and C (1-3), as well as one steroidal alkaloid, elasticine (4) and five other known compounds (5-9). Their structures were elucidated on the basis of NMR, MS, IR, UV spectroscopic data as well as by comparison with the literature. The compound 5-hydroxypyridine-3-carboxamide (9) was isolated for the first time from the Apocynaceae family. All the isolated compounds were evaluated for their antiparasitic effects against 3D7 and Dd2 strains of Plasmodium falciparum and promastigotes of Leishmania donovani (MHOM/SD/62/1S). Compounds 1-4 possessed good in vitro antimalarial activities against CQR Dd2 with IC50 values ranging from 4.68 to 5.36 µg/mL and moderate on CQS 3D7. Only compounds 1 and 2 showed leishmanicidal activities with IC50 values ranging between 10.49 and 13.21 µg/mL. In addition, crude extract exhibited potent antiplasmodial (IC50 0.91 and 3.12 µg/mL) and antileishmanial (IC50 3.32 µg/mL) activities, thus demonstrating their potential synergistic action.

Chemical constituents of the leaves of Anthonotha macrophylla (Leguminosae).

The present study deals with the isolation and the characterization of the chemical constituents from the leaves of Anthonotha macrophylla (Leguminosae). Using various chromatographic techniques (TLC, CC, HPLC), the methanolic extract of the leaves of Anthonotha macrophylla yielded one new alkaloid (1) as well as six known compounds amongst which an alkane (2), isolated for the first time from a natural product, an ester of fatty acid (3), two isocoumarines (4-5), a sterol (6) and a disaccharide (7). Their structures were elucidated using spectroscopic technics including extensive 1-D and 2-D NMR, HR-SM experiments.

Antileishmanial activity of long chain alkyl benzene and other constituents from seeds of Sesamum indicum. L (Pedaliaceae).

The methanolic extract of the waste seeds of Sesamum indicum L. (Pedaliaceae) was subjected to chromatographic fractionation; it led to the isolation of an alkyl benzene identified as 1,3-bis (pentadecyl)benzene (1) along with three known fatty acids: oleic acid (2), linoleic acid (3), and palmitic acid (4); one monosaturated cardanol, 3-pentadecylphenol (5) and two phytosteroids identified as sitostanol (6) and campestanol (7). The structures of these compounds were elucidated by chemical and spectroscopic analyses. Compounds 1, 5 and 6 were evaluated against protozoan parasites. Compound 1 moderately inhibited the promastigote form of Leishmania donovani LG13 with IC50 equal to 16.9 µM.

Farnesyl glycosides and one new triterpenoid saponin from the roots of Lecaniodiscus cupanioides Planch. ex Benth.

Chemical investigation of the methanol extract of the roots of Lecaniodiscus cupanioides led to the isolation and characterisation of three new sesquiterpene glycosides, named cupanioidesosides A (1), B (2) and C (3), together with one new triterpenoid saponin named lecanioside A (4), Their structures were established by extensive analysis of spectroscopic methods including 1D and 2D NMR techniques (COSY, NOESY, TOCSY, HSQC, and HMBC) and HRESIMS. The four new compounds were evaluated for their antiproliferative activity against the Caco-2 cell line (human epithelial cell line). None of the isolated compounds showed positive activity in our assay. Our findings represent a valuable contribution to the chemotaxonomy Lecaniodiscus genus of the subfamily of Sapindoideae of Sapindaceae family, known to be a rich source of farnesol glycosides.

Triterpenoid saponins from Calliandra calothyrsus Meisn. and their antiproliferative activity against two digestive carcinoma human cell lines.

The chemical investigation of the flowers and twigs of Calliandra calothyrsus (Fabaceae) led to the isolation of three new oleanane-type triterpenoid saponins, named calothyrsusosides AC (13). Their structures were established by direct interpretation of their spectral data, mainly HRESIMS, 1D NMR and 2D NMR (1H, 1H NMR DOSY, 13C NMR, COSY, HSQC, HMBC, HSQC-TOCSY and NOESY) and by comparison with literature data. Compounds 1 and 2 were tested for their antiproliferative activity against two digestive carcinoma human cell lines: Hep3B (hepatocellular carcinoma) and Caco-2 (epithelial colorectal adenocarcinoma). Both compounds exhibited an antiproliferative activity against the Hep3B cell line, with IC50 values of 6.0 and 6.5 µM, respectively, while no effect was detected against the epithelial colorectal adenocarcinoma Caco-2 (CC50 > 25 µM).

Synthesis and Biological Evaluation of Four New Ricinoleic Acid-Derived 1-O-alkylglycerols.

A series of novel substituted 1-O-alkylglycerols (AKGs) containing methoxy (8), gem-difluoro (9), azide (10) and hydroxy (11) group at 12 position in the alkyl chain were synthesized from commercially available ricinoleic acid (12). The structures of these new synthesized AKGs were established by NMR experiments as well as from the HRMS and elementary analysis data. The antimicrobial activities of the studied AKGs 8-11 were evaluated, respectively, and all compounds exhibited antimicrobial activity to different extents alone and also when combined with some commonly used antibiotics (gentamicin, tetracycline, ciprofloxacin and ampicillin). AKG 11 was viewed as a lead compound for this series as it exhibited significantly higher antimicrobial activity than compounds 8-10.

Lebbeckoside C, a new triterpenoid saponin from the stem barks of Albizia lebbeck inhibits the growth of human glioblastoma cells.

One new acacic acid-type saponin, named lebbeckoside C (1), was isolated from the stem barks of Albizia lebbeck. Its structure was established on the basis of extensive analysis of 1D and 2D NMR (1H, 13C NMR, DEPT, COSY, TOCSY, ROESY, HSQC and HMBC) experiments, HRESIMS studies, and by chemical evidence as 3-O-[ß-d-xylopyranosyl-(l→2)-ß-d-fucopyranosyl-(1→6)-[ß-d-glucopyranosyl(1→2)]-ß-d-glucopyranosyl]-21-O-{(2E,6S)-6-O-{4-O-[(2E,6S)-2,6-dimethyl-6-O-(ß-d-quinovopyranosyl)octa-2,7-dienoyl]-4-O-[(2E,6S)-2,6-dimethyl-6-O-(ß-d-quinovopyranosyl)octa-2,7-dienoyl]-ß-d-quinovopyranosyl}-2,6-dimethylocta-2,7-dienoyl}acacic acid 28 O-[ß-d-quinovopyranosyl-(l→3)-[α-l-arabinofuranosyl-(l→4)]-α-l-rhamnopyranosyl-(l→2)-ß-d-glucopyranosyl] ester. The isolated saponin (1) displayed significant cytotoxic activity against the human glioblastoma cell line U-87 MG and TG1 stem-like glioma cells isolated from a patient tumor with IC50 values of 1.69 and 1.44 µM, respectively.