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.     

A novel polyacetylene from the aerial parts of Artemisia lactiflora

A novel polyacetylene, artemisidiyne A (1), has been isolated from the aerial parts of Artemisia lactiflora. The structure of this compound, which consists of an unprecedented skeleton, was established by comprehensive spectroscopic analysis. Furthermore, this new compound showed cytotoxic activity against HCT-8, BGC-823, and A549 tumor cell lines with IC₅₀ values of 7.5, 1.1 and 4.6 μM, respectively.     

The synthesis and biological evaluation of some caffeic acid amide derivatives: E-2-Cyano-(3-substituted phenyl)acrylamides

A series of caffeic acid amide derivatives 2-cyano-(3-substituted phenyl)acrylamides were synthesized via Knoevenogal condensation of substituted benzaldehydes with cyanoacetamides. The structure of compound 1f was determined as E-isomer by X-ray diffractive analysis. The biological screening tests in vitro showed that compound 1b has obvious inhibitory activities against human gastric carcinoma cell line BGC-823, human nasopharyngeal carcinoma cell line KB and human hepatoma cell line BEL-7402 with IC₅₀ values of 5.6 μg/mL, 13.1 μg/mL and 12.5 μg/mL, respectively. Some preliminary structure–activity relationships (SAR) were also proposed which may provide a direction for further study.     

(−)-Menthylamine derivatives as potent and selective antagonists of transient receptor potential melastatin type-8 (TRPM8) channels

A series of twenty-two (?)-menthylamine derivatives was synthesized and tested on TRPM8, TRPV1, and TRPA1 channels. Five of the novel compounds, that is, 1d, 1f, 2b, 2c, and 2e behaved as potent TRPM8 antagonists with IC₅₀ values versus icilin and (?)-menthol between 20 nM and 0.7 μM, and were between 4- and ～150-fold selective versus TRPV1 and TRPA1 activation. Compound 1d also induced caspase 3/7 release in TRPM8-expressing LNCaP prostate carcinoma cells, but not in non-TRPM8 expressing DU-145 cells. Five other derivatives, that is, 1a, 1g, 1h, 2f, and 2h were slightly less potent than previous compounds but still relatively selective versus TRPV1 and TRPA1.     

Synthesis and biological screening of a combinatorial library of β-chlorovinyl chalcones as anticancer,anti-inflammatory and antimicrobial agents

A combinatorial library of β-chlorovinyl chalcones (4) were synthesized by Claisen–Schmidt condensation reaction. Catalytic reaction of substituted 3-chloro-3-phenyl-propenal (2) and 1-(2,4-dimethoxy-phenyl)-ethanone or 1-(4-methoxy-phenyl)-ethanone (3) in alkaline conditions furnished the target compound 5-chloro-1-(2,4-dimethoxy-phenyl)-5-phenyl-penta-2,4-dien-1-one (4). The synthesized compounds were screened for their biological activity viz. anticancer, anti-inflammatory and antimicrobial activities. Synthesized compounds 4g and 4h revealed promising anti-inflammatory activity (66–67% TNF-α and 95–97% IL-6 inhibitory activity at 10 μM). Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Furthermore, the anticancer activity (30–40%) was shown by compounds 4d, 4e, 4h and 4b at 10 μM concentrations against ACHN followed by Calu 1, Panc1, HCT116 and H460 cell lines. Some of the compounds 4d, 4e, 4a, 4i and 4b revealed promising antimicrobial activity at MIC 50–100 μg/mL against selected pathogenic bacteria and fungi.     

Synthesis and biological activity of 4-substituted benzoxazolone derivatives as a new class of sEH inhibitors with high anti-inflammatory activity in vivo

A series of novel 4-substituted benzoxazolone derivatives was synthesized, characterized and evaluated as human soluble epoxide hydrolase (sEH) inhibitors and anti-inflammatory agents. Some compounds showed moderate sEH inhibitory activities in vitro, and two novel compounds, 3g and 4j, exhibited the highest activities with IC₅₀ values of 1.72 and 1.07 μM, respectively. Structure–activity relationships (SARs) revealed that introduction of a lipophilic amino acid resulted in an obvious increase in the sEH inhibitory activity, especially for derivatives containing a phenyl (3d, IC₅₀ = 2.67 μM), pyrrolidine (3g, IC₅₀ = 1.72 μM), or sulfhydryl group (3e, IC₅₀ = 3.02 μM). Several compounds (3a–3g) were tested in vivo using a xylene-induced ear edema mouse model. Three compounds (3d, 3f, and 3g) showed strong anti-inflammatory activities in vivo which were higher than that of Chlorzoxazone, a reference drug widely used in the clinic. Our investigation provided a novel type of sEH inhibitor and anti-inflammatory agent that may lead to the discovery of a potential candidate for clinical use.     

Synthesis and biological evaluation of nitrogen-containing benzophenone analogues as TNF-α and IL-6 inhibitors with antioxidant activity

A series of nitrogen-containing benzophenone analogues were synthesized by Mannich reaction and evaluated for the inhibition of pro-inflammatory cytokines, TNF-α and IL-6. DPPH (1,1-diphenyl-2-picryl hydrazine) radical scavenging activity and its kinetics were studied to determine the antioxidant potential of the test samples. All the synthesized compounds exhibited promising activity against IL-6 in a range of 81–89%, 09–42% at 10 and 1 μM, respectively, concentration. Exceptionally, the compound 20e was observed to be an effective inhibitor of TNF-α (54%) and IL-6 (97%), (47%) at 10 and 1 μM concentrations with minimum toxicity (22%) against CCK-8 cells. With few exceptions, all other compounds were found to be excellent inhibitors of IL-6 and moderate to excellent inhibitors of TNF-α, however the toxicity profiles of these compounds need to be ameliorated in further optimization studies. Amongst the tested compounds, 16a, 17g, 18f, 18g, 19g and 20e were found to possess significant antioxidant activity.     

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.     

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.     

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.     

Novel synthetic organic compounds inspired from antifeedant marine alkaloids as potent bacterial biofilm inhibitors

In this paper, we have reported seventeen novel synthetic organic compounds derived from marine bromopyrrole alkaloids, exhibiting potential inhibition of biofilm produced by Gram-positive bacteria. Compound 5f with minimum biofilm inhibitory concentration (MBIC) of 0.39, 0.78 and 3.125 μg/mL against MSSA, MRSA and SE respectively, emerged as promising anti-biofilm lead compounds. In addition, compounds 5b, 5c, 5d, 5e, 5f, 5h, 5i and 5j revealed equal potency as that of the standard drug Vancomycin (MBIC = 3.125 μg/mL) against Streptococcus epidermidis. Notably, most of the synthesized compounds displayed better potency than Vancomycin indicating their potential as inhibitors of bacterial biofilm. The cell viability assay for the most active hybrid confirms its anti-virulence properties which need to be further researched.     

Toward discovery of mutant EGFR inhibitors; Design,synthesis and in vitro biological evaluation of potent 4-arylamino-6-ureido and thioureido-quinazoline derivatives

A new series of 4-anilinoquinazolines with C-6 ureido and thioureido side chains and various substituents at the C-4 anilino moiety was designed, synthesized and evaluated as wild type (WT) and mutant EGFR inhibitors. Most of the compounds inhibited EGFR kinase wild type (EGFR WT) with IC₅₀ values in the low nanomolar range (<0.495–9.05 nM) and displayed more potent cytotoxic effect in BaF/3 expressing EGFR WT than reference compound gefitinib. The anti-proliferative effect of all synthesized compounds against gefitinib insensitive double mutant cell lines Ba/F3 expressing Del19/T790M and Ba/F3 expressing L858R/T790M were assayed. Compounds 4d, 6f, 7e showed significant inhibition (IC₅₀ = 1.76–2.38 μM) in these mutant lines and significant Her2 enzyme inhibition (IC₅₀ = 19.2–40.6 nM) compared to lapatinib (60.1 nM). The Binding mode of compounds 6d, 6f, 7a, 7b and 8b were demonstrated. Furthermore, growth inhibition against gefitinib insensitive cell lines PC9-GR4 (Del19/T790M) were tested, compounds 6f and 7e showed about eight and three folds respectively greater potency than gefitinib. Our structure–activity relationships (SAR) studies suggested that presence of ethyl piperidino urea/thiourea at 6-position and bulky group of (3-chloro-4-(3-fluorobenzyloxy)phenyl)amino at 4-position of quinazoline may serve as promising scaffold for developing inhibitors against wild type and mutant EGFR.     

Schiff’s base derivatives bearing nitroimidazole moiety: New class of antibacterial,anticancer agents and potential EGFR tyrosine kinase inhibitors

New Schiff’s base derivatives 5a–5h have been synthesized by reaction between 1-(4-bromophenyl)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanone 3 and various benzohydrazide 4a–4h in presence of nickel (II) nitrate as a catalyst in ethanol at room temperature in good yield (54–88%). All compounds were tested for antibacterial as well as anticancer and inhibition of EGFR. Of the compounds studied, compounds 5d, 5f and 5g in the case of antiproliferation and inhibition of EGFR as well as compounds 5b, 5c, 5e and 5h in the case of antibacterial activity were found to be most effective compounds in the series. Compound 5f shows effective inhibition (IC₅₀ = 0.21 ± 0.02 μM) by binding in to the active pocket of EGFR receptor with minimum binding energy (ΔG_b = ?49.4869 kcal/mol).     

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.     

Synthesis and antibiofilm activity of marine natural product-based 4-thiazolidinones derivatives

4-Thiazolidinones derivatives of marine bromopyrrole alkaloids were synthesized as potential antibiofilm compounds. Among the synthesized compounds, some showed promising antibiofilm activity. Biological data revealed that 1,3-thiazolidin-4-one derivatives are more potent antibiofilm agents compared to 1,3-thiazinan-4-ones. Antibiofilm activity of compound 4b, 4c (MIC = 0.78 μg/ml) was 3-fold superior than standard vancomycin (MIC = 3.125 μg/ml) while activity of compound 4d, 4f, 4g and 4h was 2-fold (MIC = 1.56 μg/ml) against Staphylococcus aureus biofilm. Compound 4b–4h showed equal antibiofilm activity against Staphylococcus epidermidis compared to standard Vancomycin (MIC = 3.125 μg/ml).     

Cytotoxic cassaine diterpenoid–diterpenoid amide dimers and diterpenoid amides from the leaves of Erythrophleum fordii

Detailed phytochemical investigation from the leaves of Erythrophleum fordii resulted in the isolation of 13 compounds, including three cassaine diterpenoid–diterpenoid amide dimers (1, 3 and 5), and seven cassaine diterpenoid amides (6 and 8–13), together with three previously reported ones, erythrophlesins D (2), C (4) and 3β-hydroxynorerythrosuamide (7). Compounds 1, 3 and 5 are further additions to the small group of cassaine diterpenoid dimers represented by erythrophlesins A–D. Their structures were determined by analysis of extensive one- and two-dimensional NMR experiments and ESIMS methods. Cytotoxic activities of the isolated compounds were tested against HCT-8, Bel-7402, BGC-823, A549 and A2780 human cancer cell lines in the MTT test. Results showed that compounds 1 and 3–5 exhibited significantly selective cytotoxic activities (IC₅₀ < 10 μM) against these cells, respectively.     

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.     

Solvent free,catalyst free,microwave or grinding assisted synthesis of bis-cyclic imide derivatives and their evaluation for anticancer activity

Cyclic imides are well known to be very important antitumor agents such as mitonafide and amonafide etc. Based on this fact, we have synthesized two series of cyclic imide derivatives containing two cyclic imide moiety in their structures (bis-cyclic imides) and screened them for in vitro anticancer activity against five human cancer cell lines i.e. breast (T47D), lung (NCl H-522), colon (HCT-15), ovary (PA-1) and liver (Hep G2). One series of bis-cyclic imide derivatives (3a–h) have been synthesized by condensation of acid anhydrides (1a–b) with diamines (2a–d) and another series (9a–f, 10a–f, 11a–f and 12a–f) by condensation of various diamines (4a–f) with diacids (5–8) in good yields. Structures assigned to 3a–h, 9a–f, 10a–f, 11a–f and 12a–f were fully characterized by spectroscopic means and elemental analysis. On screening for in vitro anticancer activity, compounds 3a (breast T47D), 3d (breast T47D, liver Hep G2), 3e (breast T47D, liver Hep G2), 3h (colon HCT-15), 10f (liver Hep G2) and 11a (colon HCT-15, ovary PA-1) exhibited good anticancer activities with IC₅₀ values range from 12.41 ± 3.2 to 17.9 ± 2.5 μM.     

Design and synthesis of new potent anticancer pyrazoles with high FLT3 kinase inhibitory selectivity

A new series of 1H- and 2H-pyrazole derivatives (35 final compounds) has been designed and synthesized in this study. A selected group (13 compounds) was then tested over a panel of 60 cancer cell lines at a single dose concentration of 10 μM. At this concentration, six compounds have showed moderate to strong mean inhibitions, and were further tested at five-dose testing mode to determine their IC₅₀ over the 60 cell lines. The IC₅₀ values of the tested compounds indicated high potency (as for compound 10f) as well as high efficacy (as for compound 11e). Accordingly, compound 10f was then tested at a single dose concentration of 10 μM over a panel of 54 kinases to determine its kinase inhibitory profile. The compound has showed good selectivity towards FLT3 kinase, associated with a moderate potency, with an IC₅₀ value of 1.74 μM.     

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.