Cytotoxicity and QSAR study of (thio)ureas derived from phenylalkylamines and pyridylalkylamines

Simplified 1,3-disubstituted urea derivatives (11–24) of phenylethylamines, homoveratylamines, 2-pyridylethylamines, 2-picolylamines as well as xylylenediamines were synthesized and investigated for their cytotoxic activities. The results revealed that most analogs displayed cytotoxicity against HepG2 and MOLT-3 cell lines. The bis-thiourea derivatives 23 and 24 exhibited higher inhibitory potency against HepG2 cell than the reference drug, etoposide. 1,1′-(1,3-phenylenebis(methylene))bis(3-(4-chlorophenyl)thiourea) 24 was shown to be the most potent cytotoxic compound against MOLT-3 cell line with an IC₅₀ value of 1.62 μM. QSAR studies suggested that compounds with high ionization potential displayed high cytotoxicity against HuCCA-1 cell line. Furthermore, derivatives with dimethoxyphenyl group had high radial distribution function with a correspondingly high cytotoxicity against A549 cell line. Moreover, analogs 23 and 24 had low values of E _HOMO (energy of the highest occupied molecular orbital energy) as well as high cytotoxicity against HepG2 cell line. This study affords an easily accessible approach for the synthesis of promising anticancer agents. The developed QSAR models provided pertinent information into the physicochemical properties governing the investigated biologic properties.     

Synthesis, molecular modeling, and biological evaluation of 1,2,4-triazole derivatives containing pyridine as potential anti-tumor agents

There is an accumulating body of experimental evidences validating focal adhesion kinase (FAK) as a therapeutic target and offering opportunities for anti-tumor drug development. In present study, we sought to synthesize twenty-eight potential FAK inhibitors as anti-tumor agents based on 1,2,4-triazole skeleton. The bioassay assays demonstrated that compounds 3e and 6j showed the most potent activity, 3e inhibited the growth of HCT116 and HepG2 cell lines with IC₅₀ values of 8.17 and 7.04 μM, while compound 6j showed the most potent biological activity against HCT116 cell line (IC₅₀ = 1.99 μM). Besides, compound 6j also exhibited significant FAK inhibitory activity (IC₅₀ = 2.41 μM). The results of flow cytometry and western-blot assay demonstrated that compounds 3e and 6j possessed good anti-proliferative activity. Docking simulations were performed to position compounds 3e and 6j into the active site of FAK to determine the probable binding model.     

Synthesis and anti-cancer activity of some novel C-17 analogs of ursolic and oleanolic acids

A series of seventeen novel analogs of ursolic and oleanolic acid were synthesized (60–98 %), and evaluated for their anti-cancer potential against a panel of eight human cancer cell lines. Compounds (3–10) showed comparable or better activities than their respective parent compounds against SiHa and HeLa (Cervix), A-549 (Lung), and IMR-32 (Neuroblastoma) cancer cell lines. Significantly, among the bromoalkyl esters (11–19), compound 13 showed promising anti-cancer activity against Leukemia THP-1 cell line at 10 μM concentration. In this series, it is interesting to note that the increase in chain length has an adverse effect on the activity.     

Synthesis and cytotoxicity of novel 4-(4-(substituted)-1H-1,2,3-triazol-1-yl)-N-phenethylbenzenesulfonamides

A new series of 4-(4-(substituted)-1H-1,2,3-triazol-1-yl)-N-phenethylbenzenesulfonamide derivatives 5 were synthesized through the Click approach and evaluated for their cytotoxic activity against four cancer cell lines (HuCCA-1, HepG2, A549, and MOLT-3). Most of the synthesized triazoles 5 displayed cytotoxicity against MOLT-3 cell line, except for analogs 5a–c and 5e. Significantly, 4-phenyltriazoles (5a and 5n), 4-(naphthalen-2-yloxy)methyltriazole 5d, as well as 4-((2-oxo-2H-chromen-7-yl)oxy)methyltriazole 5l showed higher cytotoxic activity against HepG2 cells than the reference drug, etoposide. Interestingly, the 4-phenyltriazole 5a was the most potent and promising compound with IC₅₀ value of 9.07 μM against HepG2 cell line. The analog 5a also exerted the highest cytotoxic activity against HuCCA-1 cells. This finding provides the novel lead molecules for further development.     

Anti-mycobacterial, cytotoxic activities of Knoevenagel and (E)-α,β-unsaturated esters and ketones from 2-chloronicotinaldehydes

Series of 2-chloronicotinaldehyde Knoevenagel derivatives 3a–r; (E)-α,β-unsaturated esters and ketones 5a–k were prepared and evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H₃₇Rv (Mtb). Compounds 3e, 5b, 5d, 5e, 5g and 5i–k were shown potent to significant activity. Compound 5j is the most potent Mtb inhibitor (MIC: 4.89 μM) when compared to standard drugs Ethambutol (MIC: 7.63 μM) and Ciprofloxacin (MIC: 9.44 μM). Eight compounds displayed potent/significant activity against M. tuberculosis were chosen for the cytotoxicity against three cell lines (Raw 264.7, MCF7, and HeLa). Compound 5j displayed low toxicity with high selective index (15–30) and is an interesting new compound may serve for the development of therapeutics targeted against anti-mycobacterial compounds. This is the first report assigning in vitro anti-mycobacterial inhibitory activity and structure–activity relationship for this class of substituted 2-chloronicotinaldehyde derivatives and presents new family of compounds.     

Synthesis and antiproliferative activity evaluation of imidazole-based indeno[1,2-b]quinoline-9,11-dione derivatives

A series of new imidazole substituted indeno[1,2-b]quinoline-9,11-dione derivatives were synthesized and evaluated for their antiproliferative effects on HeLa, LS180, MCF-7 and Jurkat human cancer cell lines. Antiproliferative effects were evaluated using MTT assay. Prepared compounds exhibited weak to good antiproliferative activity in evaluated cell lines. Prepared compounds were more potent in Jurkat cell line when compared to LS180, HeLa and MCF-7 cell lines. Compounds 29 (IC₁₆ = 0.7 μM) and 31 (IC₁₆ = 1.7 μM) and 33 (IC₁₆ = 1.7 μM) were found to be the most potent molecules on Jurkat cell lines. Moreover; it was found that some of the tested compounds bearing imidazole-2-yl moiety on the C₁₁-position of dihydropyridine ring exhibited superior antiproliferative activity in comparison to cis-platin especially in Jurkat cell line (compounds 29, 31, and 33). It seemed that the introduction of electron-withdrawing groups on the imidazole ring enhanced the antiproliferative potential of these compounds (compounds 27, 29 and 31). The results of this study proposed that some of the imidazole substituted indeno[1,2-b]quinoline-9,11-dione compounds may act as efficient anticancer agents in vitro, emphasizing their potential role as a source for rational design of potent antiproliferative agents.     

Synthesis and cytotoxic evaluation of novel 2,3-di-O-alkyl derivatives of l-ascorbic acid

A new series of 2,3-di-O-alkyl derivatives of 5,6-O-isopropylidene-l-ascorbic acid were synthesized using phase transfer catalysis in aqueous media. These derivatives were screened for their superoxide radical scavenging activity and anticancer activity against human breast cancer cell line (MCF-7), leukemic cell line (HL-60), and cervical cell line (HeLa). All these derivatives exhibited enhanced scavenging effect than l-ascorbic acid except for the 4-fluorobenzyl or 2/4-chlorobenzyl alkyl group either at 3-O and/or 2-O position displayed pro-oxidant activity. These pro-oxidant derivatives (2c–e, m) exhibited potent anticancer activities against all the cell lines (IC₅₀ = 25.79–57.21 μM). However, these compounds were also cytotoxic to human normal leukemic macrophages THP-1. On the other hand, antioxidant derivatives displayed albeit slight (2k, IC₅₀ = 57.96–63.45 μM), but selective inhibitory effect toward all tumor cell lines. Thus, pro-oxidant and antioxidant properties can be used to predict the cytotoxic selectivity of drug against normal and cancer cells.     

A polybromodiphenyl ether from an Indonesian marine sponge Lamellodysidea herbacea and its chemical derivatives inhibit protein tyrosine phosphatase 1B, an important target for diabetes treatment

The ethanol extract of an Indonesian marine sponge Lamellodysidea herbacea inhibited the activity of protein tyrosine phosphatase 1B (PTP1B), an important target enzyme for the treatment of type II diabetes. Bioassay-guided isolation yielded a known polybromodiphenyl ether (1) as a sole bioactive component. The structure of 1 was confirmed by spectroscopic data for 1 and its methyl ether derivative (2). Compound 1 markedly inhibited the PTP1B activity (IC₅₀ = 0.85 μM) and showed a moderate cytotoxicity against two human cancer cell lines, HCT-15 (colon) and Jurkat (T-cell lymphoma) cells. On the other hand, compound 2 maintained potent inhibitory activity against PTP1B (IC₅₀ = 1.7 μM) but did not show apparent cytotoxicity at 18 μM against these cancer cells. Four ester derivatives [acetyl (3), butyryl (4), hexanoyl (5), and benzoyl (6)] were prepared from 1 and their activities evaluated against PTP1B and two cancer cell lines to investigate the structure–activity relationships. Although compounds 3–6 exhibited potent inhibitory effects against PTP1B activity, cytotoxicity against HCT-15 and Jurkat cells was observed as a similar efficacy to that of 1. From these results, compound 2 was found to be the best inhibitor of PTP1B with no apparent cytotoxicity. Therefore, 2 may be a lead compound for making a new type of PTP1B inhibitor. Moreover, compound 2 did not inhibit the cell growth of Huh-7 cells (hepatoma). Hepatocytes are one of the locations of PTP1B, and Huh-7 cells are used to study the mechanism of action of compound 2.     

Thiourea and thioether derivatives of sorafenib: synthesis, crystal structure, and antiproliferative activity

A series of novel sorafenib derivatives containing diaryl thiourea and thioether, 9a–u, was designed and synthesized, and their antiproliferative activities against HCT116 and MDA-MB-231 cell lines were also evaluated and described. Most compounds exhibited potent antiproliferative activity against HCT116 cells with IC₅₀ = 1.8–80.4 μM. Compounds 9p, 9r, and 9s demonstrated competitive antiproliferative activities to sorafenib, against all two cancer cell lines. The structures of all the newly synthesized compounds were determined by ¹H NMR, ¹³C NMR, and HRMS, and compound 9n was characterized by single-crystal X-ray diffraction. Primary structure–activity relationships (SAR) have also been established.     

Synthesis,biological evaluation,and molecular docking studies of pyrazolyl-acylhydrazone derivatives as novel anticancer agents

A series of pyrazolyl-acylhydrazone derivatives (1e–20e) have been designed and synthesized and their biologic activities were also evaluated for telomerase inhibition and tumor cell antiproliferation. Among all the compounds, 12e showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC₅₀ values of 0.57 ± 0.03 and 0.49 ± 0.07 μM, respectively. Compound 12e also exhibited significant telomerase inhibitory activity (IC₅₀ = 1.9 ± 0.43 μM). The result of flow cytometry demonstrated that compound 12e induced cell apoptosis. Docking simulation was performed to insert compound 12e into the crystal structure of telomerase at ATP binding site to determine the probable binding model. Based on the preliminary results, compound 12e with potent inhibitory activity in tumor growth may be a potential anticancer agent.     

Synthesis of novel spin-labeled podophyllotoxin derivatives as potential antineoplastic agents: Part XXV

A series of novel spin-labeled 4β-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin derivatives (17a–h) were firstly designed and synthesized with significant regioselectivity by employing Cu(I) catalyzed click approach, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU145, KB, and KBvin). Among them, compound 17h displayed the highest cytotoxic activity against the tumor cell lines tested. Significantly, compound 17h showed superior cytotoxic activity compared with etoposide (IC₅₀ 6.30 to >10 μM), a clinically available anticancer drug. Significant activity toward the drug resistant KBvin cell line revealed promising future for compound 17h as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidate.     

Steroidal saponins from the leaves of Yucca de-smetiana and their in vitro antitumor activity: structure activity relationships through a molecular modeling approach

Four steroidal saponins were isolated from the leaves of Yucca de-smetiana Baker. Their structures were established using one- and two- dimensional NMR spectroscopy and mass spectrometry. The structure of the new steroidal saponin was identified as: (25R)-3β-hydroxy-5α-spirostan-3-O-β-d-xylopyranosyl-(1 → 2)-β-d-galactopyranosyl-(1 → 2)-O-[β-d-glucopyranosyl-(1 → 3)]-β-d-glucopyranosyl-(1 → 4)-β-d-galactopyranoside (desmettianoside C) along with three known spirostanol and furostanol saponins. The isolated saponins were evaluated for their antitumor activity against HCT116, MCF7, HepG2, and A549 cell lines. Saponins 3 and 4 showed potent activity against HCT116, MCF7, and HepG2 cell lines in comparison with the positive control doxorubicin. A molecular modeling approach was performed to establish conformational criteria that could affect the biological activity of the isolated saponins.     

Anti-inflammatory activities of crocetin derivatives from processed Gardenia jasminoides

This study was designed to investigate changes of anti-oxidant and anti-nitric oxide (NO) production activities of Gardenia jasminoides (Gj) by roast processing, and anti-inflammatory activities of crocetin derivatives isolated from Gj. In order to evaluate anti-oxidant and anti-inflammatory activities, DPPH radical scavenging activities and inhibitory activities against lipopolysaccharide (LPS)-induced NO production were determined. Then we isolated crocin (1), gentiobiosyl glucosyl crocetin (3), and mono-gentiobiosyl crocetin (4) from the fruit of Gj, and crocetin (2) from the processed fruit of Gj (PGj) by column chromatography. Their structures were based on spectroscopic methods including IR, MS, and NMR (1D and 2D). Then we assayed contents of crocetin derivatives by HPLC analysis. These crocetin derivatives were evaluated the inhibitory activities on NO production in LPS-stimulated macrophage RAW 264.7 cells and expressions of protein and m-RNA of iNOS and COX-2 by western blot analysis and RT-PCR experiment. The DPPH radical scavenging activities were increased and NO productions in LPS-stimulated RAW 264.7 cells were decreased dose-dependently by processing. Crocin contents were decreased and crocetin contents were increased by processing in HPLC analysis. Compounds 1, 2, 3 and 4 reduced NO production in a dose-dependent manner with IC₅₀ values of 58.9 μM (1), 29.9 μM (2), 31.1 μM (3), and 37.6 μM (4) respectively. Crocetin (2) showed the most potent anti-inflammatory activity (IC₅₀ = 29.9 μM), and compound 3 and 4 were firstly measured for inhibitory activities on NO production. Their correlation between structure and activity was not clear but the activity of aglycone type showed the most potent activity. They also suppressed the protein and m-RNA expressions of iNOS and COX-2 in LPS-activated macrophage. These results suggest that anti-oxidant and anti-NO production activities of Gj were increased by processing, and increased anti-inflammatory activities of Gj by processing were due to the increase of crocetin, the aglycone that has greater activity than crocin.     

Alkaloids from Lycoris caldwellii and their particular cytotoxicities against the astrocytoma and glioma cell lines

Phytochemical investigation of the ethanol extract of the bulbs of Lycoris caldwellii afforded four new alkaloids, (+)-N-methoxylcarbonyl-nandigerine (1), (+)-N-methoxycarbonyl-lindcarpine (2), (+)-10-O-methylhernovine N-oxide (3), and (+)-3-hydroxy-anhydrolycorine N-oxide (4). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (¹H-¹H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. All the alkaloids were in vitro evaluated for their cytotoxic activities against eight tumor cell lines (BEN-MEN-1, CCF-STTG1, CHG-5, SHG-44, U251, BGC-823, HepG2, and SK-OV-3). Alkaloids 1 and 2 exhibited particular cytotoxic activities against astrocytoma and glioma cell lines with IC₅₀ of 9.2–11.3 μM and 10.4–12.2 μM respectively.     

Synthesis and biological evaluation of fatty imidazolines

A series of eight fatty imidazolines were synthesized under microwave-assisted conditions using different fatty acids namely octyl, decyl, dodecyl, tetradecyl and octadecyl, mixed fatty acids prepared from Sterculia foetida (containing cyclopropene-rich fatty acids), coconut (containing medium-chain-rich fatty acids), palm (containing saturated-rich fatty acids) and sunflower (containing unsaturated-rich fatty acids). Coconut, sunflower and non-edible oil S. foetida-based imidazolines were synthesized for the first time. The fatty imidazolines were evaluated for anti-fungal activity and found to be good to excellent (MIC, 4.68–18.75 μg ml^?1) against the tested Candida strains as compared with fluconazole (MIC, 16–64 μg ml^?1) as standard. The fatty imidazolines also exhibited excellent to moderate anti-bacterial activity (MIC, 4.68–75 μg ml^?1) against Staphylococcus aureus MTCC 96, S. aureus MLS 16 MTCC 2940 and Pseudomonas aeruginosa MTCC 2453 as compared with neomycin (MIC, 18.75 μg ml^?1) as standard. The cytotoxic evaluation of the imidazolines against different cancer cell lines such as HeLa (Human Cervical Cancer Cell line), A549 (Human Alveolar Adenocarcinoma Cell line), MDA-MB-231& MCF7 (Human Breast Adenocarcinoma Cell line) and Neuro2a (Mouse neuroblastoma cell line) showed excellent cytotoxicity for dodecyl (3b), tetradecyl (3c), octadecyl (3d) and coconut (3f)-based imidazolines. Sunflower-based imidazoline (3g) exhibited good anti-cancer activity towards A549, Neuro2a and palm-based imidazoline (3h) towards HeLa, A549 and MCF-7 cell lines.     

Synthesis of B-ring substituted flavones and evaluation of their antitumor and antioxidant activities

A series of flavones, substituted at the ring B, were synthesized using either Claisen–Schimdt Condensation or Baker–Venkataraman rearrangement. The synthesized compounds were tested for in vitro cytotoxic activity by sulforhodamine B assay against three cell lines of different origin, viz. HepG2, MCF-7, and MOLT-4. The compounds were also tested for a possible antioxidant activity by determination of inhibition of lipid peroxidation. Quercetin was taken as a standard for antioxidant activity. Compound 1c showed the highest cytotoxic activity against MCF-7 (GI50 < 0.1 μM) and MOLT-4 (GI50 < 0.1 μM) cell lines and was comparable to adriamycin, the standard used. Compounds 1b, 1g, and 1h also showed promising activity against MCF-7 and MOLT-4 cell lines. In the absence of a hydroxyl group, one or more methoxy groups present on the B-ring (compounds 1c–1e) were major determinants of inhibition of lipid peroxidation.     

New eremophilane-type sesquiterpenes from an Antarctic deep-sea derived fungus,Penicillium sp. PR19 N-1

Chemical investigation of an Antarctic deep-sea derived fungus Penicillium sp. PR19 N-1 yielded five new eremophilane-type sesquiterpenes 1–5 and a new rare lactam-type eremophilane 6, together with three known compounds 7–9. The structures of these diverse sesquiterpenes were determined by extensive NMR and mass spectroscopic analyses. Compounds 1, 2, 4–6, 8 and 9 were evaluated for their cytotoxities against HL-60 and A-549 human cancer cell lines, and 5 was the most active one with IC₅₀ value of 5.2 μM against the A-549 cells.     

Synthesis of novel spin-labeled derivatives of 5-FU as potential antineoplastic agents

Chemotherapy is a general treatment option for various cancers, including lung cancer. In order to find compounds with superior bioactivity and less toxicity against lung cancer, novel spin-labeled 5-fluorouracil (5-FU) derivatives (3a–f) were synthesized and evaluated against four human tumor cell lines (A-549, DU-145, KB, and KBvin). Two promising compounds 3d and 3f exhibited IC₅₀ values of 2.76 and 2.38 μM, respectively, against non-small cell lung carcinoma cell line A-549. These compounds were twofold more cytotoxic than 5-FU and less toxic against other tested cell lines. Compound 3f exhibited seven times more selective cytotoxicity against A-549 than 5-FU. Our results suggest that compounds 3d and 3f merit further investigation for development into clinical trial candidates for non-small cell lung cancer.     

Cytotoxic and anti-inflammatory constituents from the seeds of Descurainia sophia

A new sinapoyl glycoside, 1,3-di-O-sinapoyl-β-d-glucopyranose (1) along with 13 known compounds, including, sinapoyl glycosides (2 and 3), cardenolide glycoside (4), flavonoids (5–10), lignan (11), phenolic acids (12 and 13), and phytosterol (14), were isolated from the seeds of Descurainia sophia by chromatographic separation methods. The structures of 1–14 were determined by the interpretation of spectroscopic data as well as by comparison of that data with previously reported values. Compounds 2, 3, 5, 6, and 11 were identified in and isolated from this plant for the first time in this study. All isolates were evaluated for in vitro cytotoxic activities against seven human cancer cell lines and for in vitro anti-inflammatory potential using LPS-stimulated RAW264.7 murine macrophages. Compound 4 showed potent cytotoxicity (IC₅₀ values ranging from 0.034 to 0.596 μM) against all human cancer cell lines tested and was identified as the main active cytotoxic constituent of this plant. Compound 8 (ED₅₀ = 5.45 μM) and 11 (ED₅₀ = 10.02 μM) exerted dose-dependent inhibitory effects on NO production in LPS-stimulated RAW264.7 cells.