The application of Heck reaction in the synthesis of guaianolide sesquiterpene lactones derivatives selectively inhibiting resistant acute leukemic cells

A series of guaianolide-type sesquiterpene lactones derivatives with arylation of α-methylene-γ-lactone moiety was synthesized using Heck reactions, and was evaluated for their activities against acute myelogenous leukemia (AML) cell line HL-60 and doxorubicin-resistant cell line HL-60/A. Although all compounds were significantly less active against HL-60 than the parent molecules, surprisingly, compounds 3a, 4c–4e, 5e, and 8d exhibited high potency against doxorubicin-resistant cell line HL-60/A (IC₅₀ = 6.2–19 μM), and their activities against HL-60/A were comparable to that of their parent molecules. In view of their novel activities against HL-60/A, compound 5e with inhibitory activity against HL-60/A (IC₅₀ = 6.2 ± 0.5 μM) was selected for study its preliminary mechanism. The result reveals that compound 5e can obviously induce apoptosis.     

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.     

Design,synthesis and biological evaluation of millepachine derivatives as a new class of tubulin polymerization inhibitors

A series of novel tubulin polymerization inhibitors (9a–9p) have been synthesized and evaluated for their in vitro and in vivo biological activities. Among these compounds, 9e displayed strong antiproliferative activity against several tumor cell lines (IC₅₀ = 0.15–0.62 μM). Compound 9e was also shown to arrest cells in the G2/M phase of the cell cycle and inhibit the polymerization of tubulin. Molecular docking studies suggested that 9e binds into the colchicine binding site of tubulin. In xenograft experiments, 9e exerted more potent anticancer effect than anticancer drug taxol against the H460 Human lung carcinoma in BALB/c nude mice. In summary, these findings suggest that 9e is a promising new antimitotic compound for the potential treatment of cancer.     

Synthesis,molecular modeling and biological evaluation of dithiocarbamates as novel antitubulin agents

A series of novel dithiocarbamate compounds with the chalcone scaffold have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and antitubulin polymerization inhibitors. Compound 2n showed the most potent biological activity in vitro, which inhibited the growth of MCF-7 cells with IC₅₀ of 0.04 ± 0.01 μM and the polymerization of tubulin with IC₅₀ of 6.8 ± 0.6 μM. To understand the tubulin–inhibitor interaction and the selectivity of the most active compound towards tubulin, molecular modeling studies were performed to dock compound 2n into the colchicine binding site, which suggested probable inhibition mechanism.     

Recombination of diterpenoid structure units: Synthesis of antitumor amides bearing functionalized bicyclo[3.2.1]octane ring

In this work, 23 new amides (14–36) bearing a representative diterpenoid structure unit, the functionalized bicyclo[3.2.1]octane ring, have been synthesized and its antitumor potential is studied. In vitro studies demonstrate that a number of amides with the bicyclo[3.2.1]oct-3-en-2-one subunit are active against HL-60, SMMC-7721, A-549, SK-BR-3, and PANC-1 tumor cell lines. The hybrid derivative, compound 20, was found to be the most potent compound (IC₅₀ = 1.05 μM against HL-60) and more active than cisplatin (DDP), the positive control. Additionally, compound 20 exhibited broad spectrum in vitro anticancer activity with IC₅₀ values of 1.1–4.3 μM against the five tested cancer cell lines.     

Chemical constituents of Ligularia alticola Worosch. leaves and their biological activities

Seven eremophilane-type sesquiterpenes (1–7), six cycloartane derivatives (8–13) and α-amyrin acetate (14) were isolated from the leaves of the far-eastern plant Ligularia alticola Worosch. (Family Asteraceae). (4S,5R,8S,10R)-8-Ethoxyeremophil-7(11)-en-12(8)-olide (1), 8α,11-epidioxy-8β-methoxyeremophil-6-ene (2) and 29-norcycloartan-3α-ol (8) have not been previously reported. Fukinone α-epoxide (3) was isolated for the first time from a natural source. The structures of all the compounds were established by the extensive analysis of their 1D and 2D NMR spectra and HR ESI mass spectrometry. The absolute stereochemistry of 1 was determined by comparison of theoretical and experimental ECD spectra with the application of B3LYP-TDDFT and B3LYP-GIAO calculations as well as by NMR spectroscopy. Compound 1 showed cytotoxic action against human cancer HL-60, Raji, and THP-1 cell lines (IC₅₀ 12.6, 6.0 and 6.9 μM, respectively). Compounds 2 and 4 demonstrated significant cytotoxic activities against HL-60 (IC₅₀ 2.8 and 5.8 μM, respectively) and Raji cells (IC₅₀ 2.9 and 4.2 μM, respectively). Compound 6 was cytotoxic against Raji cells (IC₅₀ 4.6 μM). None of tested compounds were cytotoxic against RAW 264.7 cells. Compounds 1 and 4–7 significantly decreased intracellular ROS levels, induced by endotoxic LPS from Escherichia coli in RAW 264.7 murine macrophages.     

Design,synthesis and biological evaluation of (E)-3-(3,4-dihydroxyphenyl)acrylylpiperazine derivatives as a new class of tubulin polymerization inhibitors

A series of novel (E)-3-(3,4-dihydroxyphenyl)acrylylpiperazine derivatives had been synthesized and evaluated their biological activities as potential tubulin polymerization inhibitors. Among these compounds, compound 3q exhibited potent antiproliferative activities against three cancer cell lines in vitro, and antitubulin polymerization activity with IC₅₀ of 0.92 μM, which was superior to that of colchicine (IC₅₀ = 1.34 μM). Docking simulation was performed to insert compound 3q into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. These results suggested that compound 3q may be a promising antitubulin agent for the potential treatment of cancer.     

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.     

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.     

Synthesis,molecular modeling,and biological evaluation of cinnamic acid metronidazole ester derivatives as novel anticancer agents

A series of novel cinnamic acid metronidazole ester derivatives have been designed and synthesized, and their biological activities were also evaluated as potential EGFR and HER-2 kinase inhibitors. Compound 3h showed the most potent biological activity (IC₅₀ = 0.62 μM for EGFR and IC₅₀ = 2.15 μM for HER-2). Docking simulation was performed to position compound 3h into the EGFR active site to determine the probable binding model. Antiproliferative assay results demonstrated that some of these compounds possessed good antiproliferative activity against MCF-7. Compound 3h with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent.     

Design,synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors

Two series of afatinib derivatives bearing cinnamamide moiety (10a–n and 11a–h) were designed, synthesized and evaluated for the IC₅₀ values against four cancer cell lines (A549, PC-3, MCF-7 and Hela). Two selected compounds (10e, 10k) were further evaluated for the inhibitory activity against EGFR and VEGFR2/KDR kinases. Seven of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ values in single-digit μM to nanomole range. Three of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 10k showed the best activity against A549, PC-3, MCF-7 and Hela cancer cell lines and EGFR kinase, with the IC₅₀ values of 0.07 ± 0.02 μM, 7.67 ± 0.97 μM, 4.65 ± 0.90 μM and 4.83 ± 1.28 μM, which were equal to more active than afatinib (0.05 ± 0.01 μM, 4.1 ± 2.47 μM, 5.83 ± 1.89 μM and 6.81 ± 1.77 μM), respectively. Activity of compounds 10e (IC₅₀ 9.1 nM) and 10k (IC₅₀ 3.6 nM) against EGFR kinase were equal to the reference compound afatinib (IC₅₀ 1.6 nM). Structure–activity relationships (SARs) and docking studies indicated that replacement of the aqueous solubility 4-(dimethylamino)but-2-enamide group by cinnamamide moiety didn’t decrease the antitumor activity. The results suggested that methoxy substitution had a significant impact on the activity and methoxy substituted on C-4 or C-2,3,4 position was benefit for the activity.     

Synthesis,biological evaluation,and molecular docking studies of novel 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety as FAK inhibitors with anticancer activity

A series of 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety (3a–3r) has been designed, synthesized and their biological activities were also evaluated as potential antiproliferation and focal adhesion kinase (FAK) inhibitors. Among all the compounds, 3p showed the most potent activity in vitro which inhibited the growth of A549 with IC₅₀ value of 3.11 μM and Hela with IC₅₀ value of 2.54 μM respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC₅₀ = 0.45 μM). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model.     

Design,synthesis and biological evaluation of heterocyclic azoles derivatives containing pyrazine moiety as potential telomerase inhibitors

Three series of novel heterocyclic azoles derivatives containing pyrazine (5a–5k, 8a–8k and 11a–11k) have been designed, synthesized, structurally determined, and their biological activities were evaluated as potential telomerase inhibitors. Among the oxadiazole derivatives, compound 5c showed the most potent biological activity against SW1116 cancer cell line (IC₅₀ = 2.46 μM against SW1116 and IC₅₀ = 3.55 μM for telomerase). Compound 8h performed the best in the thiadiazole derivatives (IC₅₀ = 0.78 μM against HEPG2 and IC₅₀ = 1.24 μM for telomerase), which was comparable to the positive control. While compound 11f showed the most potent biological activity (IC₅₀ = 4.12 μM against SW1116 and IC₅₀ = 15.03 μM for telomerase) among the triazole derivatives. Docking simulation by positioning compounds 5c, 8h and 11f into the telomerase structure active site was performed to explore the possible binding model. The results of apoptosis demonstrated that compound 8h possessed good antitumor activity against HEPG2 cancer cell line. Therefore, compound 8h with potent inhibitory activity in tumor growth inhibition may be a potential antitumor agent against HEPG2 cancer cell. Therefore, the introduction of oxadiazole, thiadiazole and triazole structures reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity.     

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.     

Identification and optimization of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V3 (V1b) receptor antagonists

The discovery, synthesis, and preliminary structure–activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS? technology, had good activity in a V3 binding assay (IC₅₀ = 0.20 μM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC₅₀ = 0.31 μM) and 24 (IC₅₀ = 0.12 μM) with improved drug-like characteristics.     

Design,synthesis and anticancer activity of piperazine hydroxamates and their histone deacetylase (HDAC) inhibitory activity

Six compounds were synthesized with piperazine in linker region and hydroxamate as Zinc Binding Group (ZBG). They were screened against three cancer cell-lines (NCIH460; HCT116; U251). Compounds 5c and 5f with GI₅₀ value of 9.33 ± 1.3 μM and 12.03 ± 4 μM, respectively, were tested for their inhibitory potential on hHDAC8. Compound 5c had IC₅₀ of 33.67 μM. Compounds were also screened for their anticancer activity against HL60 human promyelocytic leukemia cell line due to the presence of pharmacophoric features of RR inhibitors in them. Compound 5c had IC₅₀ of 0.6 μM at 48 h.     

Discovery of small molecules that inhibit melanogenesis via regulation of tyrosinase expression

5,6,7,8-Tetrahydro-4H-cyclohepta[d]isoxazole derivatives were synthesized and evaluated as a novel class of inhibitors for α-melanocyte-stimulating hormone (α-MSH) induced melanogenesis in a mouse melanoma B16F10 cell line. Compound 8e (IC₅₀ = 0.67 μM), 8h (IC₅₀ = 1.01 μM) and 9b (IC₅₀ = 0.99 μM) exhibited a potent inhibitory activity approximately 85- to 126-fold greater than kojic acid, a well-known potent inhibitor. A biochemical study indicates that the activity of this series should be displayed via down-regulation of the expression of tyrosinase.     

Kojic acid derived hydroxypyridinone–chloroquine hybrids: Synthesis,crystal structure,antiplasmodial activity and β-haematin inhibition

Aminochloroquinoline–kojic acid hybrids were synthesized and evaluated for β-haematin inhibition and antiplasmodial activity against drug resistant (K1) and sensitive (3D7) strains of Plasmodium falciparum. Compound 7j was the most potent compound in both strains (IC₅₀^3D7 = 0.004 μM; IC₅₀^K1 = 0.03 μM) and had the best β-haematin inhibition activity (0.07 IC₅₀ equiv vs 1.91 IC₅₀ equiv for chloroquine). One compound 8c was found to be equipotent in both strains (IC₅₀ = 0.04 μM).     

Synthesis,chiral resolution,and determination of novel furan lignan derivatives with potent anti-tumor activity

A kind of racemic furan lignans were synthesized via a novel route, and two optical isomers were obtained through a selective hydrolization. The absolute configurations were determined by circular dichroism spectroscopy after separated through a preparative column. The different activities of isomers and the racemates were evaluated on QGY-7701 and HeLa cell lines, and compound 2c showed the best activity on QGY-7701 and HeLa cell lines with IC₅₀ 12 μM and 13 μM, respectively.     

Synthesis and biological evaluation of cinnamido linked benzophenone hybrids as tubulin polymerization inhibitors and apoptosis inducing agents

A new class of hybrid molecules containing cinnamide subunit linked to benzophenone as inhibitors of tubulin polymerization were synthesized and evaluated for their anticancer potential. These hybrids exhibit anticancer activity with IC₅₀ values ranging from 0.06 to 16.3 μM. Compounds 4f and 4g possessing fluoro and trifluoromethyl on the cinnamido subunit showed significant cytotoxic activity with IC₅₀ values 0.06 and 0.09 μM against HeLa cell line, respectively. These compounds showed cell cycle arrest at G2/M phase of the cell cycle and inhibited tubulin polymerization followed by activation of caspase-3 activity and apoptotic cell death. Further in vitro tubulin polymerization assay showed that the level of tubulin inhibition was comparable to that of 2a for the compounds 4f and 4g. Moreover, Hoechst 33258 staining and DNA fragmentation assay suggested that these compounds induce cell death by apoptosis. Overall, the current study demonstrates that the synthesis of benzophenone linked cinnamide subunit conjugates as promising anticancer agents with G2/M arrest and apoptotic-inducing ability via targeting tubulin.