Synthesis,cytotoxicity, and haemolytic activity of chacotrioside lupane-type neosaponins and their germanicane-type rearrangement products

The concise synthesis, via a stepwise glycosylation approach, of lupeol, betulin and betulinic acid O-glycosides bearing a chacotriosyl moiety at the C-3 position is described. All neosaponins as well as their rearrangement products of the germanicane-type were evaluated in vitro for their anticancer and haemolytic activities. Although betulinic acid and betulin 3β-O-chacotriosides were neither cytotoxic nor haemolytic, their rearrangement products allobetulin and 28-oxoallobetulin 3β-O-chacotriosides (9 and 10) exhibited a cytotoxicity profile up to fourfold superior to betulinic acid against human breast (MCF7) and prostate (PC-3) adenocarcinomas cell lines (IC₅₀ = 10–18 μM). One important result was that only chacotriosides featuring non-polar functions at the C-28 position (6, 9 and 10) exerted a haemolytic activity against red blood cells.     

Synthesis and biological evaluation of baicalein derivatives as potent antitumor agents

Baicalein (5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one), a major flavonoid extracted from the root of Scutellaria baicalensis Georgi (Chinese name: Huangqin), showed potent anti-proliferative activity against a broad panel of human cancer cell lines both in vitro and in vivo. A novel series of baicalein derivatives were synthesized by introducing a group to C6-OH and a nitrogen-containing hydrophilic heterocyclic ring to C7-OH via a length of 3 or 4-carbon chain in this study. The in vitro antiproliferative activities of the 30 derivatives against HepG2, A549, BCG-823 cancer cell lines were evaluated. Among them, 10 compounds exhibit more potent cytotoxicity than baicalein against the three cancer cell lines. The most potent compound 9b possesses highest anti-proliferative potency against HepG2, A549, and BCG-823 with an IC₅₀ value of 2.0 μM, 0.8 μM and 3.2 μM, respectively. Preliminary mechanism studies with compound 9b using Annexin V/PI double-staining assay and DAPI staining assay indicated that 9b inhibits tumor cell proliferation potentially through inducing apoptosis.     

Three new triterpenoid saponins from the aerial parts of Lysimachia foenum-graecum

A further phytochemical investigation of the aerial parts of Lysimachia foenum-graecum Hance led to the isolation of three new oleanane-type triterpenoid saponins, foegraecumosides L–N (1–3), along with one known saponin, 3-O-β-d-glucopyranosyl-(1 → 2)-α-l-arabinopyranosyl-cyclamiretin A (4). Their structures were elucidated by spectroscopic data analyses and chemical methods Compounds 1−4 were evaluated for their cytotoxicity against NCI-H460, MGC-803, HepG2, and T24 human cancer cell lines, and compound 4 showed moderate activity against all tested cell lines. Furthermore, the cytotoxicity of compound 4 was tested on drug-sensitive and drug-resistant lung cancer cell lines (A549 and A549/CDDP, respectively).     

Design,synthesis and biological evaluation of novel 3-substituted 4-anilino-coumarin derivatives as antitumor agents

Various 3-substituted 4-anilino-coumarin derivatives have been designed, synthesized and their anti-proliferative properties have been studied. The in vitro cytotoxicity screening was performed against MCF-7, HepG2, HCT116 and Panc-1 cancer cell lines by MTT assay. Most of the synthesized compounds exhibited comparable anti-proliferative activity to the positive control 5-Fluorouracil against these four tested cancer cell lines. Among the different substituents at C-3 position of coumarin scaffold, 3-trifluoroacetyl group showed the most promising results. Especially, compounds 33d (IC₅₀ = 16.57, 5.45, 4.42 and 5.16 μM) and 33e (IC₅₀ = 20.14, 6.71, 4.62 and 5.62 μM) showed excellent anti-proliferative activities on MCF-7, HepG2, HCT116 and Panc-1 cell lines respectively. In addition, cell cycle analysis and apoptosis activation revealed that 33d induced G2/M phase arrest and apoptosis in MCF-7 cells in a dose-dependent manner. Low toxicity of compounds 33d and 33e was observed against human umbilical vein endothelial cells (HUVECs), suggesting their acceptable safety profiles in normal cells. Furthermore, the results of in silico ADME studies indicated that both 33d and 33e exhibited good pharmacokinetic properties.     

New acyclic sesquiterpenoid derivatives and a monoterpene disaccharide from Dichondra repens Forst.

A new highly oxygenated acyclic sesquiterpenoid (2E, 6E)-8,10,11-trihydroxyl-7,11-dimethyl-3-hydroxymethyl-2,6-dodecadienoic acid (1) and its glucoside (2), together with a new pinane monoterpene disaccharide glucoside 6,6-dimethyl-2-methlenebicyclo [3.1.1]hept-3-O-(6-O-apiofuranosyl)-β-d-glucopyranoside (3) were isolated from hydrophilic extract of Dichondra repens. Their structures were elucidated on the basis of spectroscopic analyses and chemical methods. The three compounds did not show any cytotoxic activity (IC50 > 20 μM) against two human lung cancer cell lines (NCI-H661 and A549).     

Synthesis and biological evaluation of novel steroidal 5α,8α-epidioxyandrost-6-ene-3β-ol-17-(O-phenylacetamide)oxime derivatives as potential anticancer agents

Inspired by the significant anti-cancer activity of our previously screened natural ergosterol peroxide (EP, 1), we synthesized and characterized a series of novel 5α,8α-epidioxyandrost-3β-ol-17-(O-phenylacetamide)oxime derivatives (9a–o). The anti-proliferative activity of the synthesized compounds against human hepatocellular carcinoma cells (HepG2, Sk-Hep1) and human breast cancer cells (MCF-7, MDA-MB231) were investigated. Compounds 9d, 9f, 9h, 9j and 9m displayed good anti-proliferative activity (most IC₅₀ < 20 μM) in vitro. Furthermore, fluorescence imaging showed that the designed coumarin-9d conjugate (12) localized mainly in mitochondria, leading to enhanced anticancer activities over the parent structure.     

Novel 6-N-arylcarboxamidopyrazolo[4,3-d]pyrimidin-7-one derivatives as potential anti-cancer agents

A novel series of 3,5,6-trisubstituted pyrazolo[4,3-d]pyrimidin-7-one derivatives, especially 6-N-arylcarboxamidopyrazolo[4,3-d]pyrimidin-7-ones were synthesized and evaluated for their in vitro anticancer activities against various human cancer cell lines. The inhibitory activities for several kinases have also been tested. The prepared compounds library exhibited significant anticancer activity towards HT-29 colon and DU-145 prostate cancer cell lines. The structure–activity relationships of the 6-N-arylcarboxamidopyrazolo[4,3-d]pyrimidin-7-one scaffold at R¹, R² and R³ have been elucidated. Among the synthesized compounds, 12b was the most active compound with GI₅₀ value of 0.44 μM and 1.07 μM against HT-29 and DU-145 cell lines, respectively, and 13a was the most selective compound towards colon cancer cell line.     

Novel dammarane saponins from Gynostemma pentaphyllum and their cytotoxic activities against HepG2 cells

Two new dammarane saponins, 2α,3β,12β-trihydroxydammar-20(22),24-diene-3-O-[β-d-glucopyranoxyl(1→2)-β-d-6″-O-acetylglucopyranoside (1, namely damulin C) and 2α,3β,12β-trihydroxydammar-20(21),24-diene-3-O-[β-d-glucopyranoxyl(1→2)-β-d-6″-O-acetylglucopyranoside (2, namely damulin D), were isolated from the ethanol extract of Gynostemma pentaphyllum, which had been heat processed by steaming at 125 °C. The NMR spectroscopic data of the novel saponins were completely assigned by using a combination of 2D NMR experiments including ¹H–¹H COSY, HSQC, and HMBC. Their cytotoxic activities of human liver adenocarcinoma HepG2 cells were evaluated in vitro. They showed cytotoxicities against HepG2 cell line with IC₅₀ of 40 ± 0.7 and 38 ± 0.5 μg/ml, respectively.     

New cytotoxic dihydrochalcone and steroidal saponins from the aerial parts of Sansevieria cylindrica Bojer ex Hook

A new dihydrochalcone, 2‘,4‘-dihydroxy-3‘-methoxy-3,4-methylenedioxy-8-hydroxymethylene dihydrochalcone 1 and two new steroidal saponins, (25S)-ruscogenin-1-O-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranoside 2, (25S)-ruscogenin-3-O-α-l-rhamnopyranosyl-(1 → 4)-β-d-glucopyranoside 3, together with three known steroidal saponins (25S)-ruscogenin-3-O-β-d-glucopyranoside 4, (25S)-ruscogenin-1-O-α-l-rhamnopyranosyl-(1 → 2)-[β-d-xylopyranosyl-(1 → 3)]-α-l-arabinopyranoside 5 and (25R)-26-O-β-d-glucopyranosyl-furost-5-ene-1β,3β,22α,26-tetrol-1-O-α-L-rhamnopyranosyl-(1 → 2)-[β-d-xylopyranosyl-(1 → 3)]-α-l-arabinopyranoside 6 were isolated from the aerial parts of Sansevieria cylindrica. The structures of the new compounds were established by UV, IR, EI-MS, HR-ESI–MS as well as 1D (¹H,¹³C and DEPT-135) and 2D (HSQC, HMBC and TOCSY) NMR spectral analysis. The isolated compounds 1-6 were assayed for in vitro cytotoxicities against the three human tumor cell lines HT116, MCF7 and HepG2. Compound 1 showed a moderate cytotoxicity against MCF7. Compounds 2, 3 and 6 exhibited moderate cytotoxicities against the three used cell lines and compound 5 showed marked cytotoxicities against all used cell lines.     

Design,synthesis and antitumor activity of novel pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors

A novel series of 2-(3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(4-substitutedbenzylidene)acetohydrazide (12a–g) was prepared and their structures were confirmed by spectral and elemental analyses. The cytotoxic activity of the newly synthesized compounds was evaluated against breast carcinoma (MCF-7), non-small cell lung cancer (A549) and human colorectal adenocarcinoma (HT-29) cell lines using MTT and colony formation assays. The tested compounds showed a marked anticancer activity against all the tested cell lines, especially compound 12g, which was the most potent anticancer agent with half maximal inhibitory concentrations (IC₅₀) between 5.36 and 9.09 μM. Docking studies into ATP binding site of EGFR protein tyrosine kinase were performed to predict their scores and mode of binding to amino acids, In addition, the inhibitory activity of the target compounds against epidermal growth factor receptor tyrosine kinase (EGFR-TK) was evaluated. Results indicated the ability of the target compounds to inhibit EGFR-TK with half maximal inhibitory concentrations (IC₅₀) in the range of 4.18–35.88 μM. Furthermore, The most active compounds 12g, 12c and 12d were assayed against Fibroblast Growth Factor Receptor (FGFR), Insulin Receptor (IR) and Vascular Endothelial Growth Factor Receptor (VEGFR). The activity of the reported compounds warrants further optimization as novel members in cancer treatment protocols.     

Design,synthesis and anticancer activity of novel nopinone-based thiosemicarbazone derivatives

A series of new nopinone-based thiosemicarbazone derivatives were designed and synthesized as potent anticancer agents. All these compounds were identified by ¹H NMR, ¹³C NMR, HR-MS spectra analyses. In the in vitro anticancer activity, most derivatives showed considerable cytotoxic activity against three human cancer cell lines (MDA-MB-231, SMMC-7721 and Hela). Among them, compound 4i exhibited most potent antitumor activity against three cancer cell lines with the IC₅₀ values of 2.79 ± 0.38, 2.64 ± 0.17 and 3.64 ± 0.13 μM, respectively. Furthermore, the cell cycle analysis indicated that compound 4i caused cell cycle arrest of MDA-MB-231 cells at G2/M phase. The Annexin V-FITC/7-AAD dual staining assay also revealed that compound 4i induced the early apoptosis of MDA-MB-231 cells.     

Cytotoxic glucosydic iridoids from Veronica americana

Fractionation guided by the cytotoxic activity of the methanolic extract of Veronica americana led to the isolation of two new iridoids identified as 4β-hydroxy-6-O-(p-hydroxybenzoyl)-tetrahydrolinaride (1) and 10-O-protocatechuyl-catalpol (2), together with four known aromatic acids, veratric acid (3) p-methoxybenzoic acid (4), p-hydroxybenzoic acid (5) and protocatechuic acid (6). The structure of these compounds was determined by spectroscopic analysis. Iridoid glycosides 1 and 2 showed selective cytotoxic activity against the human cancer cell lines HF-6 (IC₅₀ = 0.031 and 0.066 μM, respectively) and PC-3 (IC₅₀ = 0.721 and 0.801 μM, respectively), with less sensitivity in normal MRC-5 cells (IC₅₀ = 77.103 and 1451.562 μM, respectively). Compound 1 was 9.9 times more potent than camptothecin against HF-6 cell line, while compound 2 was 4.7 times, more potent, against the same cell line, than camptothecin. The found biological efficacy of 1 and 2 allow us to propose these compounds as candidates for the development of effective anticancer therapeutic agents.     

Three new chlorinated phenolic glycosides from Przewalskia tangutica

Three new chlorinated phenolic glycosides, namely przewatangosides A-C (1-3), along with one known compound, globosumoside A (4), were isolated from the whole plants of Przewalskia tangutica. Their structures were unequivocally determined by extensive spectroscopic analysis and chemical method. The cytotoxic activities of the isolated phenolic glycosides (1-4) were evaluated against the five human cancer cell lines A549, MCF-7, SMMC-7721, HepG2 and HL-60. Przewatangoside A (1) exhibited weak cytotoxicity against SMMC-7721 with the IC₅₀ value of 38.1 μM. All the tested compounds were inactive (IC₅₀ > 50 μM) to the normal human hepatocyte cell line (L02).     

Synthesis of novel chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives via domino aldol-type/hetero Diels–Alder reaction and their cytotoxicity evaluation

New chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives have been synthesized by domino aldol-type reaction/hetero Diels–Alder reaction generated from o-quinone methide in situ from 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones with resorcinols/naphthols in the presence of 20 mol % ethylenediamine diacetate (EDDA), triethylamine (2 mL) as co-catalyst in CH₃CN under reflux conditions in good yields. The structures were established based on spectroscopic data, and further confirmed by X-ray diffraction analysis. The results showed that compounds 4h and 4j exhibited very potent cytotoxicity against human cervical cancer cell line (HeLa). Compound 4h displayed good inhibitory activity against both breast cancer cell lines, MDA-MB-231 and MCF-7. Further, the compound 4i exhibited good cytotoxicity against only MDA-MB-231, and compound 4j showed promising activity against human lung cancer cell line, A549 with IC₅₀ value of 2.53 ± 0.07 μM, which was comparable to the standard doxorubicin (IC₅₀ = 1.21 ± 0.1 μM).     

Design,synthesis and cytotoxic activities of scopoletin-isoxazole and scopoletin-pyrazole hybrids

12 novel scopoletin-isoxazole and scopoletin-pyrazole hybrids were designed, synthesized and their chemical structures were confirmed by HR-MS, IR, ¹H NMR and ¹³C NMR spectra. The anticancer activities of the newly synthesized compounds were evaluated in vitro against three human cancer cell lines including HCT-116, Hun7 and SW620 by MTT assay. The screening results showed that six compounds (9a, 9c, 9d, 12a, 18b and 18d) exhibited potent cytotoxic activities with IC₅₀ values below 20 μM. Besides, we have further evaluated the growth inhibitory activities of six compounds against the human normal tissue cell lines HFL-1. Especially, compound 9d displayed significant anti-proliferative activity with IC₅₀ values ranging from 8.76 μM to 9.83 μM and weak cytotoxicity with IC₅₀ value of 90.9 μM on normal cells HFL-1, which suggested that isoxazole-based hybrids of scopoletin were an effective chemical modification to improve the anticancer activity of scopoletin.     

Triterpenoids in Gypsophila trichotoma Wend.

A new triterpeniod saponin 3-O-β-arabinopyranosyl-(1 → 3)-[β-galactopyranosyl-(1 → 2)]-β-glucuronopyranosyl gypsogenin (1), together with the known saponin 3-O-β-xylopyranosyl-(1 → 3)-[β-galactopyranosyl-(1 → 2)]-β-glucuronopyranosyl gypsogenin (2), and three known triterpenes gypsogenic acid (3), quillaic acid (4) and gypsogenin (5) were isolated from the roots of Gypsophila trichotoma Wend. (Caryophyllaceae). Their structures were elucidated by chemical and spectral methods. Cytotoxic activity of compounds 1 and 2 were tested against seven human cancer cell lines. Compound 1 showed cytotoxic activity against all of them, while compound 2 only against two cell lines.     

Structure and biological evaluation of novel cytotoxic sterol glycosides from the marine red alga Peyssonnelia sp

Bioactivity-guided fractionation of the extract from a Fijian red alga Peyssonnelia sp. led to the isolation of two novel sterol glycosides 19-O-β-d-glucopyranosyl-19-hydroxy-cholest-4-en-3-one (1) and 19-O-β-d-N-acetyl-2-aminoglucopyranosyl-19-hydroxy-cholest-4-en-3-one (2), and two known alkaloids indole-3-carboxaldehyde (3) and 3-(hydroxyacetyl)indole (4). Their structures were characterized by 1D and 2D NMR and mass spectral analysis. The sterol glycosides inhibited cancer cell growth with mean IC₅₀ values (for 11 human cancer cell lines) of 1.63 and 1.41 μM for 1 and 2, respectively. The most sensitive cancer cell lines were MDA-MB-468 (breast) and A549 (lung), with IC₅₀’s in of 0.71–0.97 μM for 1 and 2. Modification of the sterol glycoside structures revealed that the α,β-unsaturated ketone at C-3 and oxygenation at C-19 of 1 and 2 are crucial for anticancer activity, whereas the glucosidic group was not essential but contributed to enhanced activity against the most sensitive cell lines.     

Isolation,characterization and cytotoxic activity of benzophenone glucopyranosides from Mahkota Dewa (Phaleria macrocarpa (Scheff.) Boerl)

Two benzophenone glucopyranosides have been isolated from the nut shell part of Mahkota Dewa. The structures were identified as 2,4′,6-trihydroxy-4-methoxy-benzophenone-2-O-β-d-glucoside (Mahkoside A) and 2,4′,6-trihydroxy-4-methoxy-6″-acetyl-benzophenone-2-O-β-d-glucoside (Mahkoside B). Mahkoside B was recognized as a novel compound. Furthermore, a series of benzophenone glucopyranoside derivatives (compounds 3–18) were synthesized and their bioactivities were characterized. Our results demonstrated that compound 18 has significant cytotoxicity against two esophageal cancer cell lines, stomach cancer cell line and prostate cancer cell line, with IC₅₀ less than 10 μM, indicating its potential activity against cancer cells.     

Design,synthesis, in silico and in vitro evaluation of thiophene derivatives: A potent tyrosine phosphatase 1B inhibitor and anticancer activity

A series of novel methyl 4-(4-amidoaryl)-3-methoxythiophene-2-carboxylate derivatives were designed against the active site of protein tyrosine phosphatise 1B (PTP1B) enzyme using MOE.2008.10. These molecules are also subjected for in silico toxicity prediction studies and considering their corresponding drug scores, it implied that, the molecules are promising as anticancer agents. The designed compounds were synthesized by using suitable methods and characterized. They were subjected to inhibitory activity against PTP1B and in vitro anticancer activity by MTT assay. Most of the tested compounds showed potent inhibitory activity against PTP1B, among the compounds tested, compound 5b exhibited the highest activity (IC₅₀ = 5.25 µM) and remarkable cytotoxic activity at 0.09 µM of IC₅₀ against the MCF-7 cell line. In addition to this, compound 5c also showed potential anticancer activity at 2.22 µM of IC₅₀ against MCF-7 and 0.72 µM against HepG2 cell lines as well as PTP1B inhibitory activity at IC₅₀ of 6.37 µM.     

Synthesis and anticancer activity of novel 3,4-diarylthiazol-2(3H)-ones (imines)

A series of 3,4-diarylthiazol-2(3H)-ones and three 3,4-diarylthiazol-2(3H)-imines were synthesized and evaluated for their cytotoxicity in a panel of human cancer cell lines. Compounds 21 and 22 showed potential anticancer activity against human CEM cells with IC₅₀ values of 0.12 and 0.24 μM, respectively.