Design,synthesis and anti-Alzheimer properties of dimethylaminomethyl-substituted curcumin derivatives

Eight dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized. The antioxidant test revealed that the synthesized compounds had higher free radical scavenging activity towards both 2,2-diphenyl-1-picrylhydrazyl free radicals (DPPH) (IC₅₀ 1.5–29.9 μM) and galvinoxyl radicals (IC₅₀ 4.9–41.1 μM) than the lead compound curcumin. Besides, compound 3a could effectively inhibit the Aβ self-aggregation in vitro. Investigated in phosphate-buffered solutions (pH = 7.4) in the presence or absence of 0.1% FBS 3a showed a good stability while curcumin did not. Furthermore, 3a showed a good lipophilicity (log P = 3.48), suggesting a potential ability to penetrate the blood–brain-barrier. The aqueous solubility of the hydrochloride salt of 3a (16.7 mg/mL) has also been significantly improved as compared with curcumin (<0.1 mg/mL).     

New triterpene saponins from the seed cake of Camellia Oleifera and their cytotoxic activity

Two new oleanane-type triterpene saponins, identified as 16α-hydroxy-22-O-angeloyl-23-formyl-28,31-dihydroxymethylene-olean-12-ene-3β-O-{β-d-galactopyranosyl-(1 → 2)[β-d-xylopyranosyl-(1 → 2)-α-l-arabinopyranosyl(1 → 3)]-β-d-glucopyranosiduronic acid} (oleiferasaponin B₁, 1) and 22-O-hydrocinnamoyl-23-formyl-28-dihydroxymethylene-olean-12-ene-3β-O-{β-d-glucopyranosyl-(1 → 2)[β-d-xylopyranosyl-(1 → 2)-α-l-arabinopyranosyl(1 → 3)]-β-d-glucopyranosiduronic acid} (oleiferasaponin B₂, 2), were isolated from the seed cake of Camellia oleifera Abel. Their structures were established by extensive 1D- and 2D-NMR experiments along with TOF-MS analysis and acid hydrolysis. The cytotoxicity of the isolated compounds was evaluated in four human carcinoma cell lines: A 549, SK-OV-3, SK-MEL-2 and HCT15. Both compounds 1 and 2 exhibited significantly cytotoxic activity with IC₅₀ values of 18.5 μM (A549), 11.3 μM (SK-OV-3), 13.9 μM (SK-MEL-2) and 1.6 μM (HCT15) for 1 and IC₅₀ values of 8.4 μM (A549), 6.3 μM (SK-OV-3), 9.2 μM (SK-MEL-2) and 0.8 μM (HCT15) for 2. In addition, compound 2 showed more effective cytotoxic activity than compound 1.     

Two new lignans from Gymnotheca chinensis Decne

Two new lignans, gymnothelignans V (1) and W (2), were isolated from a methanol extraction of Gymnotheca chinensis Decne. Their structures were established on the basis of extensive 1D and 2D NMR spectroscopy. Compound 1 exhibited moderate cytotoxicity against the HCT116, HCT15, A549, MCF-7 and HepG2 cancer cell lines with IC₅₀ values of 45.1 μM, 26.9 μM, 49.6 μM, 30.0 μM and 49.7 μM, respectively. Compound 2 exhibited weak cytotoxicity against the A549 cancer cell line with an IC₅₀ value of 41.3 μM.     

Design,synthesis and molecular docking of α,β-unsaturated cyclohexanone analogous of curcumin as potent EGFR inhibitors with antiproliferative activity

A type of novel α,β-unsaturated cyclohexanone analogous, which designed based on the curcumin core structure, have been discovered as potential EGFR inhibitors. These compounds exhibit potent antiproliferative activity in two human tumor cell lines (Hep G2 and B16-F10). Among them, compounds I₃ and I₁₂ displayed the most potent EGFR inhibitory activity (IC₅₀ = 0.43 μM and 1.54 μM, respectively). Molecular docking of I₁₂ into EGFR TK active site was also performed. This inhibitor nicely fitting the active site might well explain its excellent inhibitory activity.     

Multisubstituted indole–acrylonitrile hybrids as potential cytotoxic agents

A series of multisubstituted indole–acrylonitrile hybrids were designed, synthesized and evaluated for their potential cytotoxic activities. The bio-evaluation results indicated that some of the target compounds (such as 3a, 3f, 3k, 3n) exhibited good to moderate cytotoxic effect on HepG2, BCG-823, BEL-7402, and HL-7702 cell lines. Especially, the compounds 3a and 3k also exhibited high cytotoxic activities (3a, 19.38 ± 3.38 μM; 3k, 15.43 ± 3.54 μM) against the BEL-7402 cell line resistant to Taxol (>25 μM) and 5-FU (>500 μM), which might be developed as novel lead scaffold for potential anticancer agents.     

Synthesis of novel 3,5-diaryl pyrazole derivatives using combinatorial chemistry as inhibitors of tyrosinase as well as potent anticancer,anti-inflammatory agents

In the present article, we have synthesized a combinatorial library of 3,5-diaryl pyrazole derivatives using 8-(2-(hydroxymethyl)-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-2-phenyl-4H-chromen-4-one (1) and hydrazine hydrate in absolute ethyl alcohol under the refluxed conditions. The structures of the compounds were established by IR, ¹H NMR and mass spectral analysis. All the synthesized compounds were evaluated for their anticancer activity against five cell lines (breast cancer cell line, prostate cancer cell line, promyelocytic leukemia cell line, lung cancer cell line, colon cancer cell line) and anti-inflammatory activity against TNF-α and IL-6. Out of 15 compounds screened, 2a and 2d exhibited promising anticancer activity (61–73% at 10 μM concentration) against all selected cell lines and IL-6 inhibition (47% and 42% at 10 μM concentration) as in comparison to standard flavopiridol (72–87% inhibition at 0.5 μM) and dexamethasone (85% inhibition at 1 μM concentration), respectively. Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Out of 15, four 3,5-diaryl pyrazole derivatives exhibiting potent inhibitory activities against both the monophenolase and diphenolase actions of tyrosinase. The IC₅₀ values of compounds (2a, 2d, 2h and 2l) for monophenolase inhibition were determined to range between 1.5 and 30 μM. Compounds 2a, 2d, 2h and 2l also inhibited diphenolase significantly with IC₅₀ values of 29.4, 21.5, 2.84 and 19.6 μM, respectively. All four 3,5-diaryl pyrazole derivatives were active as tyrosinase inhibitors (2a, 2d, 2h and 2l), and belonging to competitive inhibitors. Interestingly, they all manifested simple reversible slow-binding inhibition against diphenolase.     

Synthesis and biological evaluation of 2′,5′-dimethoxychalcone derivatives as microtubule-targeted anticancer agents

A series of novel 2′,5′-dimethoxylchalcone derivatives including 18 new compounds were synthesized and evaluated for cytotoxicities against two human cancer cell lines, NTUB1 (human bladder cancer cell line) and PC3 (human prostate cancer cell line). All these derivatives except for 21 exhibited significant cytotoxic effect against NTUB1 and PC3 cell lines. Compounds 13 and 17 with 4-carbamoyl moiety showed potent inhibitory effect on growth of NTUB1 and PC3 cells. Flow cytometric analysis demonstrated that treatment of NTUB1 cells with 1 μM 13 and 17 induced G1 phase arrest accompanied by an increase in apoptotic cell death of NTUB1 cells after 24 h. Treatment of PC3 cells with 1 μM and 3 μM 13, and 1 μM and 3 μM 17 induced S and G1, and G1 and G2/M phase arrests, respectively, accompanied by an increase in apoptotic cell death. These data suggested that 13 and 17 with different 4-carbamoyl moiety displayed same cell cycle arrest in NTUB1 cells while different doses of 13 and 17 revealed different cell cycle arrest in PC3 cells. Cell morphological study of 17 indicated that more cells rounding up or dead associated with tubulin polymerization. Compound 17 showed an increased α-tubulin level in polymerized microtubule fraction in a dose-dependent manner while 500 nM paclitaxel also showed similar effect in NTUB1 cells by Western blot analysis. The result suggested that 17 may be used as microtubule-targeted agents.     

Two new rotenoids from the roots of Millettia speciosa

Two new rotenoids, named millettiaosas A–B (1–2), together with four known compounds were isolated from the roots of Millettia speciosa. Their structures were elucidated on the basis of spectroscopic analysis including 1D and 2D NMR techniques and HRESIMS. Evaluation of the two new compounds for cytotoxicity against four human cancer cell lines (MCF-7, HCT-116, A549 and HepG-2) showed moderate activities (10 μM < IC₅₀ < 26 μM).     

Terpenoids with cytotoxic activity from the branches and leaves of Pyrus pashia

Twenty terpenoids, including a new triterpenoid (1) and a new monoterpenoid (20), were isolated from the branches and leaves of Pyrus pashia. The structures of two new compounds were determined to be 2α, 3β, 27-trihydroxyolean-12-en-28-oic acid (1) and (4α)-3-(5,5-dimethyltetrahydrofuranyl)-1-buten-3-ol 3-O-β-d-glucopyranoside (20) on the basis of spectroscopic analysis (IR, HRESIMS, 1D and 2D NMR) and chemical method. Some of the isolated compounds were evaluated for their cytotoxic activity against a panel of human cancer cell lines by MTT assay, using cisplatin as a positive control. Compound 14 exhibited cytotoxic activities against A549 (IC₅₀ = 19.18 ± 4.26 μM), Hela (IC₅₀ = 12.56 ± 3.89 μM), SGC7901 (IC₅₀ = 10.48 ± 1.95 μM) and NHI-1975 (IC₅₀ = 7.38 ± 2.31 μM) cell lines as well as compound 12 displayed cytotoxic activities against A549 (IC₅₀ = 14.71 ± 1.47 μM) and Hela (IC₅₀ = 12.22 ± 1.88 μM) cell lines.     

Synthesis,biological evaluation and molecular modeling of 1,3,4-thiadiazol-2-amide derivatives as novel antitubulin agents

A series of 1,3,4-thiadiazol-2-amide derivatives (6a–w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC₅₀ values of 0.03 μM, 0.06 μM and 0.05 μM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC₅₀ = 1.73 μM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.     

Synthesis,and docking studies of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (14a–e, 15a–g, 16a–e and 17a–g) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7). Four selected compounds (15e, 16a–b and 17a) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Eleven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC₅₀ values of 0.14 ± 0.08 μM, 0.24 ± 0.07 μM and 0.02 ± 0.01 μM, which were 4.6, 1.6 and 473.5 times more active than Foretinib (0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What’s more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity.     

5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones as potential anticancer agents with anti-inflammatory properties

A series of novel 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones (3a–z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI₅₀ = 850 nM), against leukemia SR cancer cells (GI₅₀ = 1.45 μM), and OVCAR-3 (GI₅₀ = 1.26 μM) ovarian cancer cell lines. The structurally related compound 3s had a GI₅₀ value of 1.77 μM against MDA-MB-435 cells. The N-naphthoyl analogue 3t had GI₅₀ values of 1.30 and 1.91 μM against HOP-92 non-small cell lung cancer and MDA-MB-435 melanoma cell lines, respectively. The related analogue 3w had GI₅₀ values of 1.09 μM against HOP-92 non-small cell lung cancer cell lines. Interestingly, docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands with strong hydrophobic and hydrogen bonding interactions. Thus, compounds 3k, 3t, 3s, and 3w constitute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer therapy.     

Novel pyrazoline derivatives as bi-inhibitor of COX-2 and B-Raf in treating cervical carcinoma

Twenty four pyrazoline derivatives modified from Celecoxib were designed and synthesized as bi-inhibitor of COX-2 and B-Raf. They were evaluated for their COX-1/COX-2/B-Raf inhibitory and anti-proliferation activities. Compound A3 displayed the most potent activity against COX-2 and HeLa cell line (IC₅₀ = 0.008 μM; GI₅₀ = 19.86 μM) and showed superb COX-1/COX-2 selectivity (>500), being more potent and selective than positive control Celecoxib or 5-fluorouracil. Compounds A5 and B5 were introduced best B-Raf inhibitory activities (IC₅₀ = 0.15 μM and 0.12 μM, respectively). Compound A4 retained superb bioactivity against COX-2 and HeLa cell line (IC₅₀ = 0.015 μM; GI₅₀ = 23.82 μM) and displayed moderate B-Raf inhibitory activity (IC₅₀ = 3.84 μM). Docking simulation was conducted to give binding patterns. QSAR models were built using bioactivity data and optimized conformations to provide a future modification of COX-2/B-Raf inhibitors.     

Cytotoxic abietane-derivative diterpenoids of Salvia lachnostachys

A bioassay-guided fractionation of Salvia lachnostachys Benth leaf extract led to the isolation of three known diterpenes, namely fruticuline A (1), fruticuline B (2) and 7,20-dihydrofruticuline A (3), together with two new compounds, 4 and 5. The structures were mainly elucidated by 1D and 2D NMR spectroscopy and HRESIMS. The cytotoxic activity of the crude ethanol extract, the semi-purified fractions (A-E) and compounds 1, 2 and 4 were evaluated against seven human cancer cell lines and the normal cell line HaCat. The ethanol extract showed activity against all tested cell lines (GI₅₀ 25.0⿿44.0 μg/mL). Among the fractions, the greatest activity was exhibited by fraction A (eluted with hexane), which inhibited the growth of all tested cell lines with GI₅₀ of 3.9⿿19.5 μg/mL. Compounds 1 and 4 were the most active, inhibiting the growth of U251, MCF-7, NCI-ADR/RES, 786.0, NCI-H460, PC-3, OVCAR-03 and HaCat cell lines with GI₅₀ < 10 μM. Compound 2 showed moderate activity against MCF-7, NCI-H460, OVCAR-03, K562 and HaCat, with GI₅₀ varying 19.9⿿29.3 μM.     

Design,synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a–e, 13a–f, 14a–f and 15a–i) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC₅₀ values of 1.04 ± 0.11 μM, 0.02 ± 0.01 μM and 9.11 ± 0.55 μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC₅₀ values: 0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.     

Synthesis and antiproliferative activities of quebecol and its analogs

Simple and efficient synthesis of quebecol and a number of its analogs was accomplished in five steps. The synthesized compounds were evaluated for antiproliferative activities against human cervix adenocarcinoma (HeLa), human ovarian carcinoma (SK-OV-3), human colon carcinoma (HT-29), and human breast adenocarcinoma (MCF-7) cancer cell lines. Among all the compounds, 7c, 7d, 7f, and 8f exhibited antiproliferative activities against four tested cell lines with inhibition over 80% at 75 μM after 72 h, whereas, compound 7b and 7g were more selective towards MCF-7 cell line. The IC₅₀ values for compounds 7c, 7d, and 7f were 85.1 μM, 78.7 μM, and 80.6 μM against MCF-7 cell line, respectively, showing slightly higher antiproliferative activtiy than the synthesized and isolated quebecol with an IC₅₀ value of 104.2 μM against MCF-7.     

Synthesis and cytotoxic potential of heterocyclic cyclohexanone analogues of curcumin

A series of 18 heterocyclic cyclohexanone analogues of curcumin have been synthesised and screened for their activity in both adherent and non-adherent cancer cell models. Cytotoxicity towards MBA-MB-231 breast cancer cells, as well as ability to inhibit NF-κB transactivation in non-adherent K562 leukemia cells were investigated. Three of these analogues 3,5-bis(pyridine-4-yl)-1-methylpiperidin-4-one B1, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidin-4-one B10, and 8-methyl-2,4-bis((pyridine-4-yl)methylene)-8-aza-bicyclo[3.2.1]octan-3-one C1 showed potent cytotoxicity towards MBA-MB-231, MDA-MB-468, and SkBr3 cell lines with EC₅₀ values below 1 μM and inhibition of NF-κB activation below 7.5 μM. The lead drug candidate, B10, was also able to cause 43% of MDA-MB-231 cells to undergo apoptosis after 18 h. This level of activity warrants further investigation for the treatment of ER-negative breast cancer and/or chronic myelogenous leukemia as prototypical cellular models for solid and liquid tumors.     

Synthesis and evaluation of some new pyrazoline substituted benzenesulfonylureas as potential antiproliferative agents

Twenty six new pyrazoline substituted benzenesulfonylureas (2a–z) were synthesized and tested for in vitro anticancer activity. Fourteen derivatives (2i, 2k–2p, 2r, 2s–2x) were screened for their antiproliferative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). Among them four compounds (2i, 2n, 2v and 2x) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM). The compounds 2i, 2n, 2v and 2x showed effective growth inhibition (GI₅₀ MID) values of 2.62, 3.93, 3.33, 3.74 μM respectively beside cytostatic activity TGI (MG-MID) values of 8.42, 65.80, 24.00 and 36.06 μM respectively. The compound 2i displayed remarkable antiproliferative activity in 8 different cell lines with GI₅₀ less than 2 μM. Compounds 2n, 2v and 2x also displayed good antiproliferative activity against 11, 18 and 14 different cell lines respectively with GI₅₀ less than 3 μM.     

Lactarane sesquiterpenoids from Lactarius subvellereus and their cytotoxicity

Subvellerolactones B (1), D (2), and E (3), structurally unusual lactarane sesquiterpenoids, were isolated from the fruiting bodies of Lactarius subvellereus together with four known lactarane sesquiterpenes (4–7). The chemical structures and stereochemistries of compounds 1–3 were determined on the basis of spectroscopic analyses, including 1D and 2D NMR experiments and a convenient Mosher ester procedure. Subvellerolactone B (1) exhibited cytotoxicity against the A549, SK-MEL-2, and HCT-15 cell lines with IC₅₀ values of 26.5, 18.3, and 14.2 μM, respectively, and subvellerolactones D (2) and E (3) showed cytotoxicity against the A549 and HCT-15 cell lines (IC₅₀ (2): 25.1 and 17.8 μM, and IC₅₀ (3): 19.6 and 28.7 μM, respectively).     

Pseudo-disesquiterpenoids from seeds of Vernonia anthelmintica and their biological activities

Three new pseudo-disesquiterpenoids, vernodalidimer F – H (1 – 3), which are formed by esterification of two sesquiterpenoids, along with a new sesquiterpenoid (4) and two known sesquiterpeonids (5, 6) were isolated from the seeds of Vernonia anthelmintica. Their structures were elucidated by NMR data. The absolute configurations of 1–3 and 5 were determined by comparison of the experimental and calculated electronic circular dichroism spectra. Cytotoxicity of the isolated compounds against four human tumor cell lines were assayed. 5 exhibited strong cytotoxicity against HCT-15, PC-3, A549 and Hela cells lines with IC₅₀ values of 5.3, 5.6, 6.2, and 8.2 μM, respectively. 2 showed non-concentration dependent cytotoxicity against HCT-15, PC-3, and A549 cells lines with inhibition rate of 56.1%, 55.3%, and 50.1%, respectively. 1 and 3 showed moderate cytotoxicity against four cell lines with IC₅₀ values ranging from 12.2 ± 5.1 to 28.6 ± 2.5 μM. The influence of melanin content in B16 melanoma cells of 1, 5, and 6 were tested, and they increased melanin content by 43.6%, 28.1%, and 37.0% higher than positive control 8-methoxypsoralen.