Synthesis, structure, anticancer, and antioxidant activity of para-xylyl linked bis-benzimidazolium salts and respective dinuclear Ag(I) N-heterocyclic carbene complexes (Part-II)

The article describes synthesis, characterization (NMR, FT-IR, microanalysis, X-ray crystallography), in vitro anticancer, and antioxidant activity of para-xylyl linked bis-benzimidazolium salts and respective dinuclear Ag–NHC complexes. All the compounds were tested for their cytotoxicity against human colorectal cancer cells (HCT 116) and DPPH antioxidant evaluation. According to cell viability measurements using MTT assay, all the tested compounds showed dose-dependent cytotoxic activity against HCT 116 cells. The tested compounds demonstrated significant activity with IC₅₀ values range 0.29–3.30 μM for HCT 116 and % age inhibition 6.37–21.00 for DPPH antioxidant study. 5-Fluorouracil was used as standard drug (IC₅₀ 19.2 μM for HCT 116) whereas for DPPH analysis, Gallic acid was used as positive control (% age inhibition 77.68). All the compounds showed potential anticancer activity against human colorectal cancer whereas antioxidant activity was not significant. We found that as the size of N-alkyl substitution on benzimidazolium salt increases its cytotoxicity against cancer decreases whereas a reverse occurs in case of respective complexes.     

Isoflavanones from Desmodium oxyphyllum and their cytotoxicity

Two new isoflavanones, (3R)-7-hydroxy-4′-methoxy-5-methoxycarbonyl-isoflavanone (1) and (3R)-8-hydroxy-4′-methoxy-7-methoxycarbonyl-isoflavanone (2), together with seven known isoflavanones (3–9) were isolated from Desmodium oxyphyllum of the Leguminosae family. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compound 1 showed good cytotoxicity against NB4 and SHSY5Y cell lines with IC₅₀ values of 3.1 and 2.5 μM; compound 2 exhibited cytotoxicity against PC3 cell lines with a IC₅₀ value of 3.6 μM; compound 4 showed cytotoxicity against A549 and SHSY5Y cell lines with IC₅₀ values of 3.6 and 2.8 μM; and compound 5 displayed cytotoxicity against NB4, SHSY5Y, and MCF7 cell lines with IC₅₀ values of 2.6, 3.8, and 2.8 μM, respectively. Other compounds also showed moderate cytotoxicity for some tested cell lines with IC₅₀ values between 5.4 and 8.8 μM.     

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 and in vitro cytotoxic evaluation of new triazole derivatives based on artemisinin via click chemistry

The paper presents the synthesis of new artemisinin triazole derivatives via click chemistry and their in vitro cytotoxic evaluation against four cancer cell lines including MCF-7, LU-1, HL-60 and P388. The bioassay result showed that most of the target compounds were active against four cell lines, in which compounds 11g displayed the most potent inhibitory activity against HL-60 cell line with IC₅₀ value of 2.5 μM.     

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.     

Synthesis,cytotoxicity, and molecular docking of substituted 3-(2-methylbenzofuran-3-yl)-5-(phenoxymethyl)-1,2,4-oxadiazoles

A series of new benzofuran/oxadiazole hybrids ( 8a – n ) was synthesized from 2H-chromene-3-carbonitriles ( 3a – c ) through the multistep synthetic methodology, and these hybrids are known to exhibit anticancer activities. All the compounds were evaluated for their in vitro cytotoxicity against the HCT116 and MIA PaCa2 cell lines. Compounds 6a (IC₅₀: 9.71 ± 1.9 μM), 6b (IC₅₀: 7.48 ± 0.6 μM), and 6c (IC₅₀: 3.27 ± 1.1 μM) displayed a significant cytotoxic activity, whereas compounds 8d and 8e exhibited good activity against both cell lines. The depletion of glycogen synthase kinase-3β (GSK3β) induces apoptosis through the inhibition of basal NF-κB activity in HCT116 colon cancer cells and MIA PaCa2 pancreatic cancer cells. Molecular docking of compounds 6a , 6b , 6c , 8d , and 8e with GSK3β demonstrated the best binding affinity, correlating with the biological activity assay. Furthermore, the structure–activity relationship of these novel compounds reveals promising features for their use in anticancer therapy.     

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.     

5-(4-Methoxybenzylidene)thiazolidine-2,4-dione-derived VEGFR-2 inhibitors: Design,synthesis, molecular docking,and anticancer evaluations

A novel series of 5-(4-methoxybenzylidene)thiazolidine-2,4-dione derivatives, 5a–g and 7a–f , was designed, synthesized, and evaluated for their anticancer activity against HepG2, HCT116, and MCF-7 cells. HepG2 and HCT116 were the most sensitive cell lines to the influence of the new derivatives. In particular, compounds 7f , 7e , 7d , and 7c were found to be the most potent derivatives of all the tested compounds against the HepG2, HCT116, and MCF-7 cancer cell lines. Compound 7f (IC₅₀ = 6.19 ± 0.5, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively) exhibited a higher activity than sorafenib (IC₅₀ = 9.18 ± 0.6, 8.37 ± 0.7, and 5.10 ± 0.4 µM, respectively) against HepG2 and MCF-7, cells but a lower activity against HCT116 cancer cells, respectively. Also, this compound displayed a higher activity than doxorubicin (IC₅₀ = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively) against HepG2 and MCF-7 cells, but nearly the same activity against HCT116 cells, respectively. All derivatives, 5a–g and 7a–f , were evaluated for their inhibitory activities against vascular endothelial growth factor receptor-2 (VEGFR-2). Among them, compound 7f was found to be the most potent derivative that inhibited VEGFR-2 at an IC₅₀ value of 0.12 ± 0.02 µM, which is nearly the same as that of sorafenib (IC₅₀ = 0.10 ± 0.02 µM). Compounds 7e , 7d , 7c , and 7b exhibited the highest activity, with IC₅₀ values of 0.13 ± 0.02, 0.14 ± 0.02, 0.14 ± 0.02, and 0.18 ± 0.03 µM, respectively, which are more than the half of that of sorafenib. Furthermore, molecular docking was performed to investigate their binding mode and affinities toward the VEGFR-2 receptor. The data obtained from the docking studies highly correlated with those obtained from the biological screening.     

Anti-inflammatory and antiproliferative prenylated chalcones from Hedysarum gmelinii

Abstract

Five new prenylated chalcones hedysarumines C-G (1–5), along with eight known chalcones (6–13) all of which were isolated from the genus Hedysarum for the first time, were isolated from the roots of Hedysarum gmelinii by chromatographic methods. Their structures were determined by extensive spectroscopic techniques. The isolated chalcones (2–13) and previously isolated prenylated chalcones (14–16) were evaluated for antiproliferative activity against five human cancer cell lines (HepG2, A549, Du145, BGC823, and HCT116) and in vitro anti-inflammatory activity. Compounds 5, 10, and 15 inhibited NO production induced by lipopolysaccharide in BV-2 cells, with IC₅₀ values ranging from 3.25 to 8.48 μM. Compounds 4 and 11 showed moderate antiproliferative activity to selective human cancer cell lines, with the IC₅₀ values of 4 and 11 against A549 cell line being 7.79 and 9.67 μM, respectively, and the IC₅₀ value of 11 against HCT116 cell line being 8.85 μM.     

Two new compounds from the broth of the marine fungus Penicillium griseofulvum Y19-07

Two new compounds, 4-hydroxyphenethyl methyl succinate (1) and 4-hydroxyphenethyl 2-(4-hydroxyphenyl)acetate (2), were isolated from the EtOAc extract of the broth of the marine fungus Penicillium griseofulvum Y19-07. Five known compounds were also obtained in this study. The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopy and mass spectrometry. All of the isolates were evaluated for their scavenging properties toward the 2,2-diphenyl-1-picrylhydrazyl free radical by spectroscopic assays. Also, in the cytotoxicity assay of the two new compounds against HL-60 and PC-3 prostate cancer cell lines, compound 2 showed potential activity with an IC₅₀ value of 64.5 μM against human HL-60 cancer cells.     

Design,Synthesis, and Biological Evaluation of Pyrazole Derivatives

In this in vitro study, a series of novel pyrazole derivatives were designed, synthesized, and evaluated against five human cancer cell lines (PC3, A549, HL60, HCT116, and SW620) for their antiproliferative and p53‐MDM2 binding inhibitory activities. Although biological evaluations showed that this series of compounds possessed weak p53‐MDM2 inhibitory activities, most of them displayed moderate to potent antiproliferative activities against the tested cells lines. Compound 11c exhibited the best potency for MDM2 (FP‐IC₅₀ = 29.22 μm ) and demonstrated antiproliferative activities in response to the five tested cell lines (IC₅₀ = 4.09–16.82 μm ). Compared with the positive control Nutlin‐1, there was enhanced antiproliferative activity to p53‐mutated or p53‐deficient cell lines (SW620, HL60, and PC3).     

Steroid constituents from the soft coral Sinularia microspiculata

A methanol extract of the soft coral Sinularia microspiculata revealed five sterols, including two new compounds. Using combined chromatographic and spectroscopic experiments, the new compounds were found to be 7-oxogorgosterol (1) and 16α-hydroxysarcosterol (2). Their structures were determined on the basis of spectroscopic data (¹H and ¹³C NMR, HSQC, HMBC, ¹H-¹H COSY, NOESY, and FT-ICR-MS) and by comparing obtained results to the values indicated in previous studies. Among the isolated compounds, 3 showed weak cytotoxic effects against HL-60 (IC_50? = 89.02 ± 9.93?μM) cell line, whereas 5 was weakly active against HL-60 (IC_50? = 82.80 ± 13.65?μM) and SK-Mel2 (IC_50? = 72.32 ± 1.30?μM) cell lines.     

Design and synthesis of novel nucleobase-based barbiturate derivatives as potential anticancer agents

Cancer today remains one of the most deadly diseases in the world. In search of novel anticancer agents, a series of newly hybrid molecules were designed and synthesized by combining the structural features of nucleobase and barbiturate derivatives using the concept of green chemistry. This approach was accomplished efficiently using the aqueous medium to give the corresponding products in a high yield. The newly synthesized compounds were characterized by spectral analysis FT-IR, ¹H NMR, ¹³C-NMR, HMBC, MASS and elemental analysis. Evaluations of these molecules over four cell lines panel of human cancer cells have identified several compounds with significant anticancer activities against one or more cell lines. Compounds TBC and TBA proved to exhibit a wide cytotoxic effect on the tested four cell lines at (IC₅₀ 16–24 μM) and (IC₅₀ 25–34 μM), respectively. Other compounds, e.g., 1,3-BA, showed a selective cytotoxicity against HepG2 at 7 μM. Taken together, this study has led to the development of a convenient, a highly yielded, and an environmentally friendly synthetic method of highly promising leads for cancer fighting.     

Cytotoxic dibenzocyclooctadiene lignans from Kadsura coccinea

Three new dibenzocyclooctadiene lignans, kadusurain A–C (1–3), together with two known compounds kadsuphilin A (4) and B (5), were isolated from an EtOAc fraction of the 80 % acetone extract of Kadsura coccinea (Lem.) A. C. Smith. Their structures were established by 1D and 2D NMR techniques, and mass spectroscopy. Anti-proliferative effect of isolated compounds was evaluated against four human tumor cell lines (A549, HCT116, HL-60, and HepG2), and it was found that compound 1 exhibited significant antiproliferative effects with IC₅₀ values ranging from 1.05 to 12.56 μg/ml.     

Synthesis and cytotoxicity evaluation of novel podophyllotoxin derivatives

Seven benzylamino derivatives of podophyllotoxin 8a–8g were synthesized and their chemical structures were confirmed by IR, ¹H‐NMR, ¹³C‐NMR and ESI‐MS spectral analyses. Their abilities to inhibit the growth of cancer cells A549, HCT‐116 and HepG2, were investigated by MTT assay. Compound 8b possessed the highest cytotoxicity on cancer cell lines with average IC₅₀ values of 3.8 µM. All we synthetic compounds were cytotoxic against three cancer cell lines at the micromolar range, indicating podophyllotoxin derivatives with structural modification of benzylamino possess potent antitumor activity.     

Chemical constituents of the red alga Laurencia tristicha

Six new sesquiterpenes, 10-hydroxy-epiaplysin (1), 10-hydroxy-aplysin (2), 10-hydroxy-debromoepiaplysin (3), aplysin-9-ene (4), epiaplysinol (5) and debromoepiaplysinol (6), together with 13 known compounds (7–19), have been isolated from the red alga Laurencia tristicha. The structures of 1–6 were determined by spectroscopic methods including IR, EI-MS, HREI-MS, and 1D and 2D NMR techniques. All compounds were obtained from this species for the first time and were tested for cytotoxic activities against several human cancer cell lines including lung adenocarcinoma (A549), stomach cancer (BGC-823), hepatoma (Bel 7402), colon cancer (HCT-8) and HeLa cell lines. Compound 6 showed selective cytotoxicity against HeLa cell line with IC₅₀ 15.5 μM, cholest-5-en-3β,7α-diol (14) was toxic to all tested cell lines with IC₅₀ values of 16.8, 5.1, 0.5, 0.5, and 0.3 μM, respectively, and other compounds were inactive (IC₅₀>10 μg/ml).     

Synthesis and in vitro antitumor activities of lupeol dicarboxylic acid monoester derivatives

Ten lupeol dicarboxylic acid monoester derivatives as new potent antitumor agents were synthesized and evaluated for in vitro antitumor activities against A549, LAC, HepG2 and HeLa cell lines. Among them, compounds 1–5 showed excellent antitumor activities against all tested tumor cell lines and compounds 6–10 exhibited high activities against A549, HepG2 and HeLa cells, exceeded lupeol, lupanol and doxorubicin. Compound 2 displayed the highest potent antitumor activities with IC₅₀ values of 5.78 μM against A549 cell, 2.38 μM against LAC cell, 6.14 μM against HepG2 cell and 0.00842 μM against HeLa cell.     

Synthesis of some 1,3,4-thiadiazole derivatives as inhibitors of Entamoeba histolytica

In the quest for potent anti-amoebic agents, some 1,3,4-thiadiazole derivatives were synthesized and characterized by spectral data. The purity of the compounds was confirmed by elemental analysis. All the compounds were screened in vitro against HM1:IMSS strain of Entamoeba histolytica by microdilution method. The results revealed that compounds 1 (IC₅₀ = 0.670 μM), 3 (IC₅₀ = 1.60 μM) and 8 (IC₅₀ = 0.522 μM) had much better anti-amoebic activity than the reference drug metronidazole (IC₅₀ = 1.80 μM). Further, cytotoxicity of the compounds having IC₅₀ value less than metronidazole was assessed by MTT assay on human breast cancer MCF-7 cell line and all the compounds were found low cytotoxic in the concentration range of 2.5–250 μM. Preliminary results indicate that these three compounds (1, 3 and 8) may be subjected to further investigations and it may be hoped that the present study will stimulate efforts towards the development of novel effective anti-amoebic agents.     

Synthesis,in vitro antiplasmodial and antiproliferative activities of a series of quinoline–ferrocene hybrids

Series of quinoline–ferrocene hybrids containing various linkers were synthesized and evaluated for antimalarial and anticancer activities as well as cytotoxicity. The hybrids with rigid linkers were found to be inactive, while those with flexible spacers showed activity against both the D10 and Dd2 strains of Plasmodium falciparum, and demonstrated a good selectivity towards these parasitic cells in comparison with emetine. The hybrid 16, featuring 3-aminopropyl methylamine linker, was the most antimalarial active compound, exhibiting a significantly better potency than chloroquine against the Dd2 strain (IC₅₀ = 0.008 vs. 0.148 μM; 19-fold), and was also found to be significantly more active than the equimolar chloroquine–ferrocene combination (IC₅₀ = 3.7 vs. 41 ng/ml, tenfold) against the Dd2 strain. Anticancer activity screening showed that all the antimalarial active hybrids also exhibited potent cytostatic (GI₅₀ = 0.6–3.3 μM) and had good cytotoxic effects (LC₅₀ = 6–8 μM) against all three cancer cell lines. The hybrid 11 possessing 1,4-butanediamine linker was distinctively the most antiproliferative of all. It was found to be more cytostatic (GI₅₀: 0.7 vs. 5.9 μM, eightfold) and (LC₅₀: 6.4 vs. 92.6 μM, 14-fold) more cytotoxic than etoposide against the TK10 (renal) cell line.