Design,synthesis and biological evaluation of novel hydroxamic acids bearing artemisinin skeleton

A series of novel hydroxamic acids bearing artemisinin skeleton was designed and synthesized. Some compounds in this series exhibited moderate inhibition against the whole cell HDAC enzymes. Especially, compound 6g displayed potent cytotoxicity against three human cancer cell lines, including HepG2 (liver cancer), MCF-7 (breast cancer) and HL-60 (leukemia cancer), with IC₅₀ values of 2.50, 2.62 and 1.28 μg/mL, respectively. Docking studies performed with two potent compounds 6a and 6g using Autodock Vina showed that both compounds bound to HDAC2 with relatively high binding affinities from −7.1 to 7.0 kcal/mol compared to SAHA (−7.4 kcal/mol). It was found in this research that most of the target compounds seemed to be more cytotoxic toward blood cancer cells (HL-60) than liver (HepG2), and breast (MCF-7) cancer cells.     

Synthesis of new morpholine-connected pyrazolidine derivatives and their antimicrobial,antioxidant, and cytotoxic activities

A simple and convenient one-pot four-component synthesis of morpholine-connected pyrazolidine derivatives 2a–f and 4a–f was developed using direct metal-free catalysis, with the identities of the synthesized compounds confirmed by IR, NMR (¹H and ¹³C), mass spectrometry, and elemental analysis. The prepared compounds were inspected for antimicrobial, antioxidant, and cytotoxic activities.Antimicrobial and antifungal activities against five bacterial and four fungal pathogens, respectively, were investigated using the disc diffusion technique. In antibacterial activity, compounds 2d and 2f (MIC = 2 μg/mL) exhibited significantly higher activity than the standard ciprofloxacin. The results of antifungal assay showed that the activity of compound 4a (MIC = 0.5 μg/mL) was significantly higher than the standard clotrimazole. Antioxidant activity was screened based on ABTS⁺ radical scavenging and linoleic acid peroxidation performance. Compound 4a showed substantial antioxidant (91.3%) activities, as compared with the Trolox standard. Cytotoxicity was evaluated using HepG2 (liver), HeLa (cervical), and MCF-7 (breast) cancer cell lines, with high toxicities observed for 2b (GI₅₀ = 12.2 μm) and 4a (GI₅₀ = 07.8 μm).     

Iodine catalyzed three component synthesis of 1-((2-hydroxy naphthalen-1-yl)(phenyl)(methyl))pyrrolidin-2-one derivatives: Rationale as potent PI3K inhibitors and anticancer agents

A series of 1-((2-hydroxynaphthalen-1-yl)(phenyl)(methyl))pyrrolidin-2-one derivatives by an efficient iodine catalyzed domino reaction involving various aromatic aldehydes, 2-pyrrolidinone and β-naphthol was achieved and the structures were elucidated by FTIR ¹H NMR, ¹³C NMR, and HRMS. Subsequently they were evaluated for cytotoxicity against breast cancer (MCF-7), colon cancer (HCT116) cell lines. In the cytotoxicity, the relative inhibition activity was remarkably found to be high in MCF-7 cell lines as 79% (4c), 83% (4f) and the IC₅₀values were 1.03 µM (4c), 0.98 µM (4f). Compounds 4a, 4e, 4k–m, and 4q were found to be inactive and rest showed a moderate activity. In order to get more insight into the binding mode and inhibitor binding affinity, compounds (4a–q) were docked into the active site phosphoinositide 3-kinase (PI3K) (PDB ID: 4JPS) which is a crucial regulator of apoptosis or programmed cell death. Results suggested that the hydrophobic interactions in the binding pockets of PI3K exploited affinity of the most favourable binding ligands (4c and 4f: inhibitory constant (ki) = 66.22 nM and 107.39 nM). The SAR studies demonstrated that the most potent compounds are 4c and 4f and can be developed into precise PI3K inhibitors with the capability to treat various cancers.     

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.     

Design and synthesis of piperazine acetate podophyllotoxin ester derivatives targeting tubulin depolymerization as new anticancer agents

In this paper, a series of podophyllotoxin piperazine acetate ester derivatives were synthesized and investigated due to their antiproliferation activity on different human cancer cell lines. Among the congeners, C5 manifested prominent cytotoxicity towards the cancer cells, without causing damage on the non-cancer cells through inhibiting tubulin assembly and having high selectively causing damage on the human breast (MCF-7) cell line (IC₅₀ = 2.78 ± 0.15 μM). Treatments of MCF-7 cells with C5 resulted in cell cycle arrest in G2/M phase and microtubule network disruption. Moreover, regarding the expression of cell cycle relative proteins CDK1, a protein required for mitotic initiation was up-regulated. Besides, Cyclin A, Cyclin B1 and Cyclin D1 proteins were down-regulated. Meanwhile, it seems that the effect of C5 on MCF-7 cells apoptosis inducing was observed to be not obvious enough. In addition, docking analysis demonstrated that the congeners occupy the colchicine binding pocket of tubulin.     

Novel carbazole sulfonamide derivatives of antitumor agent: Synthesis,antiproliferative activity and aqueous solubility

The current optimization of IG-105 (3) on the carbazole-ring provided a series of new carbazole sulfonamides derivatives 13a–13m. All of the compounds have been evaluated against HepG2 cells (hepatoma cancer) for antiproliferative activity. Compounds that showed activity better or comparable to that of 3 versus HepG2 were evaluated against MCF-7 (breast cancer), MIA PaCa-2 (pancreatic cancer), and Bel-7402 (hepatoma/liver cancer) for antiproliferative activity. Of the seven compounds selected for further study five (13b, 13g, 13j, 13k and 13l) were found to give IC₅₀ values against the four cell lines comparable to those for 3. Two compounds (13f and 13i) were more active than 3 and their activity against HepG2 and MCF-7 (IC₅₀:0.01–0.07 μM) approached that of the positive controls podophyllotoxin (podo) and CA-4. Most of compounds showed aqueous solubility (0.11–19.60 μg/mL at pH 7.4 and 2.0) better than 3. These promising results warrant further development of new compounds 13f and 13i as potential potent antitumor drug candidates.     

Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy

By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a–l contained 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these enzymes (compound 9d exhibited the best inhibitory potency on wild-type EGFR, HDAC1, and HDAC6 with IC₅₀ values 0.12 nM, 0.72 nM and 3.2 nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC₅₀ values between 0.49 and 8.76 μM). Further mechanistic study revealed that compound 9d also regulated the phosphorylation of EGFR and HER2 and histone H3 hyperacetylation on the cellular level and induced remarkable apoptosis in BT-474 cells. Therefore, our study suggested that a system network-based multi-target drug design strategy might provided an alternate drug design method, by taking into account the synergy effect of EGFR, HER-2 and HDAC.     

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 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.     

Synthesis,activity and docking studies of phenylpyrimidine–carboxamide Sorafenib derivatives

Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC₅₀ values of 6.35 ± 0.43 μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC₅₀ values of 3.39 ± 0.37 μM. Structure–activity relationships (SARs) and docking studies indicated that the second series (17a–p) showed more active than the first series (16a–g). What’s more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.     

New antiproliferative 7-(4-(N-substituted carbamoylmethyl)piperazin-1-yl) derivatives of ciprofloxacin induce cell cycle arrest at G2/M phase

New N-4-piperazinyl derivatives of ciprofloxacin 2a–g were prepared and tested for their cytotoxic activity. The primary in vitro one dose anticancer assay experienced promising cytotoxic activity against different cancer cell lines especially non-small cell lung cancer. Independently, compounds 2b, 2d, 2f and 2g showed anticancer activity against human non-small cell lung cancer A549 cells (IC₅₀ = 14.8, 24.8, 23.6 and 20.7 μM, respectively) compared to the parent ciprofloxacin (IC₅₀ >100 μM) and doxorubicin as a positive control (IC₅₀ = 1 μM). The flow cytometric analysis for 2b showed dose dependent G₂/M arrest in A549 cells. Also, 2b increased the expression of p53 and p21 and decreased the expression of cyclin B1 and Cdc2 proteins in A549 cells without any effect on the same proteins expression in WI-38 cells. Specific inhibition of p53 by pifithrin-α reversed the G₂/M phase arrest induced by the 2b compound, suggesting contribution of p53 to increase. Taken together, 2b induced G₂/M phase arrest via p53/p21 dependent pathway. The results indicate that 2b can be used as a lead compound for further development of new derivatives against non-small cell lung cancer.     

Neo-tanshinlactone D-ring modified novel analogues induce apoptosis in human breast cancer cell via DNA damage

Neo-tanshinlactone (NTL) a natural product is known for its specificity and selectivity towards the breast cancer cells. By NTL D-ring modification approach, 13 new analogues were synthesized (1A–1M). Among them 1J showed the best anticancer activity in MCF-7 (ER+, PR+/?, HER2?), SKBR3 (ER?, PR?, HER2+) and MDA-MB-231 (ER?, PR?, HER2?) cells lines with IC₅₀ value 11.98 nM, 23.71 nM, and 62.91 nM respectively. 1J showed minor grove binding interaction with DNA at AT-rich region and induced DNA double strand breaks (DDSBs). This had triggered several key molecular events involving, activation of ATM, Chk2 and p53, reduction in mitochondrial potential (Δψ_m) leading to caspase-3 and PARP cleavage mediated apoptosis. These results along with other biochemical studies strongly suggest that novel NTL analogue 1J caused DNA cleavage mediated apoptosis in the breast cancer cells and this may serve as potential lead for future breast cancer treatment.     

Synthesis and anthelmintic activity of arctigenin derivatives against Dactylogyrus intermedius in goldfish

To control the parasitic disease of Dactylogyrus intermedius, a series of new arctigenin derivatives were designed, synthesized and tested in our study. The anthelmintic activity of most of the derivatives ranged from 1 to 10 mg/L. Compared to traditional drug praziquantel (EC₅₀ = 2.69 mg/L), ether derivatives 2g and 2h exhibited slightly higher anti-parasitic activity, with the EC₅₀ values of 2.48 and 1.52 mg/L, respectively. Furthermore, the arctigenin-imidazole hybrids 4a and 4b also removed D. intermedius effectively, with the EC₅₀ values of 2.13 and 2.07 mg/L, respectively. The structure-activity relationship analysis indicated that four carbon atoms length of linker and imidazole substitute group could significantly increase the anthelmintic activity, and reduced the toxicity. Through the scanning electron microscope observation, compounds 4a and 4b caused the D. intermedius tegumental damage such as intensive wrinkles, holes and nodular structures. Overall, the structural optimization analysis of arctigenin suggested that 4a and 4b can be used for preventing and controlling Dactylogyrus infections and considered as promising lead compounds for the development of commercial drugs.     

Synthesis,anticancer activity and DNA-binding properties of novel 4-pyrazolyl-1,8-naphthalimide derivatives

A novel series of 4-pyrazolyl-1,8-naphthalimide derivatives have been designed and facilely synthesized. For anticancer activity in vitro, most of the compounds were found to be more toxic against human mammary cancer cells (MCF-7) than human cervical carcinoma cells (Hela) and human lung cancer cells (A549). Compounds 4i, 4h, 4b and 4a showed improved cytotoxic activity against MCF-7 cells over amonafide, in particular compounds 4i and 4h, the IC₅₀ values of which against cell lines of MCF-7 were 0.51 μM and 0.79 μM, respectively. The DNA-binding properties of 4i were investigated by UV–vis, fluorescence, and Circular Dichroism (CD) spectroscopies and thermal denaturation. The results indicated that compound 4i as the DNA-intercalating agent exhibited middle binding affinity with CT-DNA.     

Design,synthesis, and bioactivities of novel oxadiazole-substituted pyrazole oximes

A series of novel pyrazole oxime derivatives containing a substituted oxadiazole group were designed and synthesized. The bioassay results indicated that some title compounds displayed good acaricidal and insecticidal activities against Tetranychus cinnabarinus, Aphis medicaginis, Oriental armyworm, and Nilaparvata lugens. Especially, compounds 7a, 7b, and 7c had 80%, 90%, and 90% insecticidal activities against A. medicaginis at 20 μg/mL, respectively. Interestingly, some of the designed compounds displayed wonderful fungicidal activities in vivo against cucumber Pseudoperonospora cubensis. Furthermore, compounds 7a (EC₅₀ = 4.97 μg/mL) and 7h (EC₅₀ = 0.51 μg/mL) showed excellent fungicidal activity against P. cubensis comparable or better than that of the control Pyraclostrobin (EC₅₀ = 4.59 μg/mL).     

Synthesis and anticancer activity of novel quinoline–docetaxel analogues

A series of novel quinoline–docetaxel analogues (6a–6g, 13a–13g) were designed and synthesized by introducing bioactive quinoline scaffold to C2′-OH of docetaxel. The anticancer activities of these novel analogues were investigated against different human cancer cell lines including Hela, A549, A2780, MCF-7 and two resistant strains A2780-MDR and MCF-7-MDR. The data showed these analogues possessed similar to better cytotoxicity than docetaxel. Compound 6c was found to be the most potent one, and its IC₅₀ value against MCF-7-MDR was 8.8 nM (IC₅₀ of docetaxel was 180 nM). The work indicated that the introduction of quinolyl group in docetaxel could enhance cytotoxicity and reduce drug-resistance.     

Design,synthesis, biological evaluation and molecular docking studies of novel 3-aryl-4-anilino-2H-chromen-2-one derivatives targeting ERα as anti-breast cancer agents

The estrogen receptor (ER) has played an important role in breast cancer development and progression and is a central target for anticancer drug discovery. In order to develop novel selective ERα modulators (SERMs), we designed and synthesized 18 novel 3-aryl-4-anilino-2H-chromen-2-one derivatives based on previously reported lead compounds. The biological results indicated that most of the compounds presented potent ERα binding affinity and possessed better anti-proliferative activities against MCF-7 and Ishikawa cell lines than the positive control tamoxifen. The piperidyl substituted compounds such as 16d and 18d demonstrated strong ERα binding affinities and excellent anti-proliferative activities respectively. Compound 18d displayed the most potent ERα binding affinity with RBA value of 2.83%, while 16d exhibited the best anti-proliferative activity against MCF-7 cells with IC₅₀ value of 4.52 ± 2.47 μM. Further molecular docking studies were also carried out to investigate binding pattern of the newly synthesized compounds with ERα. All these results together with the structure–activity relationships (SARs) indicated that these 3-aryl-4-anilino-2H-chromen-2-one derivatives with basic side chain could serve as promising leads for further optimization as novel SERMs.     

Synthesis,antimycobacterial activity and docking study of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives and related hydrazide-hydrazones

A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–g and coumarin containing hydrazide-hydrazone analogues 4a–e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28–1.69 μM, which were comparable to those of isoniazid. The cytotoxicity (IC₅₀ > 200 µM) to the “normal cell” model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–e, was noticeably milder compared to that of their hydrazone analogues 4a–e (IC₅₀ 33–403 µM). Molecular docking studies on compounds 4a–e and 5b–g were also carried out to investigate their binding to the 2-trans-enoyl-ACP reductase (InhA) enzyme involved in M. tuberculosis cell wall biogenesis. The binding model suggested one or more hydrogen bonding and/or arene-H or arene-arene interactions between hydrazones or pyrazole-fused coumarin derivatives and InhA enzyme for all synthesized compounds.     

Design,synthesis and biological activities of tetrandrine and fangchinoline derivatives as antitumer agents

The isolation and modification of natural products is always a very important resources to anti-tumor drugs. Therefore, a novel series of tetrandrine and fangchinoline derivatives were designed and synthesized, and their antiproliferative activities against HepG2, MCF-7 cells were evaluated and described. From the activity result obtained, high to very high activity in vitro has been found, one of the tested compounds (compound 5d) exhibited the most significant cytotoxic effects. Compound 5d increased 29.2, 7.37 times anti-proliferative activity for HepG2 cells and MCF-7 cells compared to sunitinib (IC₅₀ = 16.06 μM and 25.41 μM). Finally flow cytometry determined that compound 5d could indeed inhibit the proliferation of HepG2 cells via inducing apoptosis.     

Syntheses of conformationally restricted benzopyran based triarylethylenes as growth inhibitors of carcinoma cells

A series of conformationally restricted benzopyran based triarylethylenes has been synthesized and characterized as potential growth inhibitors of breast carcinoma cells. The synthesized compounds (14a–b, 15a and 16a–e) presented significant growth inhibition of ER+ and ER− breast cancer cells within the range of IC₅₀ 0.55–9.96 µM. Amongst other, 16c showed potent anticancer activity at IC₅₀ 0.95 µM in MCF-7 cells with good selectivity (Selectivity Index 4.47) towards healthy cells. The mechanistic studies for 16c were performed to elucidate possible mode of action which showed 16c elicited anticancer activity through necroptosis process.