Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety

A series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC₅₀ value of 2.84 μM. Compounds 8k and 8n displayed highly effective antitumor activities against MCF-7 cells, with IC₅₀ values of 4.56 and 4.25 μM, respectively. Compounds 8a and 8n exhibited significant antiproliferative activity against A549 cells, with IC₅₀ values of 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for modulating antiproliferative activities against various tumor cell lines.     

Synthesis and evaluation of some new pyrazoline substituted benzenesulfonylureas as potential antiproliferative agents

Twenty six new pyrazoline substituted benzenesulfonylureas (2a–z) were synthesized and tested for in vitro anticancer activity. Fourteen derivatives (2i, 2k–2p, 2r, 2s–2x) were screened for their antiproliferative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). Among them four compounds (2i, 2n, 2v and 2x) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM). The compounds 2i, 2n, 2v and 2x showed effective growth inhibition (GI₅₀ MID) values of 2.62, 3.93, 3.33, 3.74 μM respectively beside cytostatic activity TGI (MG-MID) values of 8.42, 65.80, 24.00 and 36.06 μM respectively. The compound 2i displayed remarkable antiproliferative activity in 8 different cell lines with GI₅₀ less than 2 μM. Compounds 2n, 2v and 2x also displayed good antiproliferative activity against 11, 18 and 14 different cell lines respectively with GI₅₀ less than 3 μM.     

New phenolic glycosides with cyclooxygenase inhibition from the roots of Tecoma mollis

Three new phenolic glycosides (1–3) together with nine known ones were isolated from the roots of Tecoma mollis using DPPH radical scavenging bioassay-guided chromatographic separation. The structures of the new compounds were established using extensive spectroscopic data and HR-MS. The antioxidant, COX-2 inhibition, and cytotoxic activities were evaluated for the isolated compounds. Compound 4 displayed the strongest radical scavenging activity relative to ascorbic acid with IC₅₀ 8.7 μM. Compounds 5, 6, and 10 showed promising COX-2 inhibitory action, IC₅₀ values of 11.3 μM, 9.4 μM, and 13.4 μM, respectively. All compounds exhibited weak cytotoxic activity against Hela and A549 cancer cell lines.     

Design,synthesis, topoisomerase I & II inhibitory activity,antiproliferative activity,and structure–activity relationship study of pyrazoline derivatives: An ATP-competitive human topoisomerase IIα catalytic inhibitor

A series of pyrazoline derivatives (5) were synthesized in 92–96% yields from chalcones (3) and hydrazides (4). Subsequently, topo-I and IIα-mediated relaxation and antiproliferative activity assays were evaluated for 5. Among the tested compounds, 5h had a very strong topo-I activity of 97% (Camptothecin, 74%) at concentration of 100 μM. Nevertheless, all the compounds 5a–5i showed significant topo II inhibitory activity in the range of 90–94% (Etoposide, 96%) at the same concentration. Cytotoxic potential of these compounds was tested in a panel of three human tumor cell lines, HCT15, BT474 and T47D. All the compounds showed strong activity against HCT15 cell line with IC₅₀ at the range of 1.9–10.4 μM (Adriamycin, 23.0; Etoposide, 6.9; and Camptothecin, 7.1 μM). Moreover, compounds 5c, 5f and 5i were observed to have strong antiproliferative activity against BT474 cell lines. Since, compound 5d showed antiproliferative activity at a very low IC₅₀ thus 5d was then selected to study on their mode of action with diverse methods of ATP competition assay, ATPase assay and DNA-topo IIα cleavable complex assay and the results revealed that it functioned as a ATP-competitive human topoisomerase IIα catalytic inhibitor. Further evaluation of endogenous topo-mediated DNA relaxation in cells has been conducted to find that, 5d inhibited endogenous topo-mediated pBR322 plasmid relaxation is more efficient (78.0 ± 4.7% at 50 μM) than Etoposide (36.0 ± 1.7% at 50 μM).     

A novel sesquiterpene quinone from Hainan sponge Dysidea villosa

A new sesquiterpene quinone, 21-dehydroxybolinaquinone (5), together with two known related analogues, bolinaquinone (6) and dysidine (7), had been isolated from the Hainan sponge Dysidea villosa. The structure of the new compound 5 was elucidated on the basis of detailed analysis of spectroscopic data and by comparison with related model compounds. Compounds 5–7 were evaluated for the inhibitory activity against hPTP1B, a potential drug target for treatment of type-II diabetes and obesity, and cytotoxic activity against Hela cell line. The results showed that dysidine (7) had the strongest hPTP1B inhibitory activity with an IC₅₀ value of 6.70 μM and 6 had significant cytotoxic activity against Hela cell line with an IC₅₀ value of 5.45 μM. New compound 5 showed moderate PTP1B inhibitory activity and cytotoxicity with IC₅₀ values of 39.50 and 19.45 μM, respectively.     

Cytotoxic acridone and indoloquinazoline alkaloids from Zanthoxylum poggei

Two new alkaloids, poggeicridone (1) and 2-methoxy-7,8- dehydroruteacarpine (6), together with nine known compounds, were isolated from the dichloromethane (DCM) extract of the bark of Zanthoxylum poggei (Engl.) P. G. Waterman. The structures of all compounds were determined by comprehensive spectroscopic analyses (1D and 2D NMR and EI- and ESI⿿MS). Compounds 5-9 exhibited strong suppressive effects on the phagocytosis response upon activation with serum opsonized zymosan in the in vitro oxidative burst studies using whole blood. The IC₅₀ values were in the range of 12.0⿿25.9 μM. These compounds displayed a moderate level of cytotoxic activity against the human Caucasian prostate adenocarcinoma cell line PC-3, with IC₅₀ values of 15.8 and 22.1 μM (the IC₅₀ value of the positive control standard doxorubicin was IC₅₀ 0.9 μM). All isolated compounds were also tested against plant pathogenic bacteria, fungi and oomycetes using the paper disk agar diffusion assay, resulting in no significant activities (MICs > 1 mg/mL).     

Anticancer and α-chymotrypsin inhibiting diterpenes and triterpenes from Salvia leriifolia

Salvialeriol (1), a new abietane-type diterpene, was isolated from Salvia leriifolia Benth. (Salvia leriaefolia), along with two known abietane-type diterpenoids, 6-hydroxysalvinolone (2) and deacetylnemorone (3), and two known triterpenes, 2-acetoxylupeol (4), and lupine-2,3-diol (5). Compounds 2–5 are reported here for the first time from this species. Compound 4 was previously reported as a synthetic derivative of 5 and this is the first report of its isolation from a natural source. Compounds 2, 3 and 5 exhibited a potent antiproliferative activity against the prostate cancer cell lines (PC3) with IC₅₀ of 3.9 ± 0.1, 6.2 ± 0.1 and 2.8 ± 0.1 μM, respectively, and cervical cancer cell lines (HeLa) with IC₅₀ of 8.0 ± 0.3, 2.6 ± 0.1 and 2.7 ± 0.1 μM, respectively. Whereas compounds 1 and 4 showed moderate antiproliferative activities against the cell lines. Compounds 1–5 were also evaluated for the inhibition of α-chymotrypsin, a protease enzyme, and 2 exhibited a competitive inhibition of the enzyme (IC₅₀ = 188.8 μM).     

Design,synthesis and biological evaluation of some novel benzothiazole/benzoxazole and/or benzimidazole derivatives incorporating a pyrazole scaffold as antiproliferative agents

In an aim at developing new antiproliferative agents, new series of benzothiazole/benzoxazole and/or benzimidazole substituted pyrazole derivatives 11a-c, 12a-c and 13a-c were prepared and evaluated for their antiproliferative activity against breast carcinoma (MCF-7) and non-small cell lung cancer (A549) cell lines. The target compound, 2-acetyl-4-[(3-(1H-benzimidazol-2-yl)-phenyl]-hydrazono-5-methyl-2,4-dihydropyrazol-3-one (12a) was the most active compound against both MCF-7 and A549 cell lines with half maximal inhibitory concentrations (IC₅₀) = 6.42 and 8.46 μM, respectively. Furthermore, the inhibitory activity of the all the target compounds against COX enzymes was recorded as a proposed mechanism for their antiproliferative activity. The obtained results revealed that the benzothiazolopyrazolone derivative 13c was the most potent COX-2 inhibitor (IC₅₀ = 0.10 μM), while the 5-acetylbenzimidazolylpyrazolone derivative 12a was the most COX-2 selective (S.I. = 104.67) in comparison with celecoxib (COX-2 IC₅₀ = 1.11 μM, S.I. = 13.33). Docking simulation on the most active compounds 12a and 13c had been performed to investigate the binding interaction of these active compounds within the binding site of COX-2 enzyme. Collectively, this work demonstrated the promising activity of the newly designed compounds as leads for further development into antiproliferative agents.     

New coumestan and coumaronochromone derivatives from Dalbergia boehmii Taub. (Fabaceae)

Chemical investigation of leaves and heartwood of Dalbergia boehmii resulted in the isolation of two new phenolic compounds, designated dalbergestan (1) and dalbergichromone (2), along with eleven known compounds, carpachromene (3), proanthocyanidin A-2 (4); piceatannol (5); biochanin A (6); macckiain (7); homopterocarpin (8); angolensin (9); medicarpin (10); 2′,7-dihydroxy-4′,5′-dimethoxyisoflavone (11); 2′-methoxyformononetin (12); and genistein (13). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses including, IR, UV, 1D and 2D – NMR as well as HRMS data. Some of the isolated compounds were evaluated for their in vitro insulin secretion activity on isolated mice islets, leishmanicidal activity against L. major (DESTO) promastigotes and in vitro cytotoxicity on MCF-7 cell lines. All tested compounds were inactive on glucose-stimulated insulin secretion at stimulatory glucose (20.0 mM) from MIN6 cells. Compounds 3 (IC₅₀, 70.0 μg/ml), 6 (IC₅₀, 60.3 μg/ml), 7 (IC₅₀, 86.5 μg/ml) and 13 (IC₅₀, 62.6 μg/ml) exhibited low leishmanicidal activity while compound 12 (IC₅₀, 56.8 μg/ml) displayed a moderate activity. Compounds 3 and 5 were found to be active against MCF-7 at 50 μM with IC₅₀ value 33.2 ± 3.79 μg/ml and 42.64 ± 5.05 μg/ml respectively.     

Design,synthesis and molecular docking of α,β-unsaturated cyclohexanone analogous of curcumin as potent EGFR inhibitors with antiproliferative activity

A type of novel α,β-unsaturated cyclohexanone analogous, which designed based on the curcumin core structure, have been discovered as potential EGFR inhibitors. These compounds exhibit potent antiproliferative activity in two human tumor cell lines (Hep G2 and B16-F10). Among them, compounds I₃ and I₁₂ displayed the most potent EGFR inhibitory activity (IC₅₀ = 0.43 μM and 1.54 μM, respectively). Molecular docking of I₁₂ into EGFR TK active site was also performed. This inhibitor nicely fitting the active site might well explain its excellent inhibitory activity.     

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.     

Synthesis of aminoquinazoline derivatives and their antiproliferative activities against melanoma cell line

The synthesis of a novel series of aminoquinazoline derivatives 1a–r and their antiproliferative activities against A375 human melanoma cell line were described. Among them, six compounds showed superior antiproliferative activities to Sorafenib as a reference compound. In particular, the representative compound 1q bearing chromen-4-one moiety exhibited excellent antiproliferative activity (IC₅₀ = 0.006 μM) and good selectivity over HS27 fibroblast cell line.     

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.     

New antimalarials with a triterpenic scaffold from Momordica balsamina

Bioassay-guided fractionation of the methanol extract of Momordica balsamina led to the isolation of three new cucurbitane-type triterpenoids, balsaminols C–E (1–3). Their structures were elucidated on the basis of spectroscopic methods including 2D NMR experiments (COSY, HMQC, HMBC and NOESY). Balsaminols C–E, together with ten cucurbitacins isolated from the same plant (4–13), were evaluated for their antimalarial activity against the Plasmodium falciparum chloroquine-sensitive strain 3D7 and the chloroquine-resistant clone Dd2. Most of the compounds displayed antimalarial activity. Compounds 9 and 12 revealed the highest antiplasmodial effects against both strains (IC₅₀ values: 4.6, and 7.4 μM, 3D7, respectively; 4.0, and 8.2 μM, Dd2, respectively). Structure–activity relationships are discussed. Furthermore, the preliminary toxicity toward human cells of compounds 1–5 and 9 was investigated in breast cancer cell line (MCF-7). Compounds were inactive or showed weak toxicity (IC₅₀ values >19.0).     

Search for novel histone deacetylase inhibitors. Part II: Design and synthesis of novel isoferulic acid derivatives

Previously, we described the discovery of potent ferulic acid-based histone deacetylase inhibitors (HDACIs) with halogeno-acetanilide as novel surface recognition moiety (SRM). In order to improve the affinity and activity of these HDACIs, twenty seven isoferulic acid derivatives were described herein. The majority of title compounds displayed potent HDAC inhibitory activity. In particular, IF5 and IF6 exhibited significant enzymatic inhibitory activities, with IC₅₀ values of 0.73 ± 0.08 and 0.57 ± 0.16 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against human cancer cells. Especially, IF6 displayed promising profile as an antitumor candidate with IC₅₀ value of 3.91 ± 0.97 μM against HeLa cells. The results indicated that these isoferulic acid derivatives could serve as promising lead compounds for further optimization.     

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.     

Cytotoxic abietane-derivative diterpenoids of Salvia lachnostachys

A bioassay-guided fractionation of Salvia lachnostachys Benth leaf extract led to the isolation of three known diterpenes, namely fruticuline A (1), fruticuline B (2) and 7,20-dihydrofruticuline A (3), together with two new compounds, 4 and 5. The structures were mainly elucidated by 1D and 2D NMR spectroscopy and HRESIMS. The cytotoxic activity of the crude ethanol extract, the semi-purified fractions (A-E) and compounds 1, 2 and 4 were evaluated against seven human cancer cell lines and the normal cell line HaCat. The ethanol extract showed activity against all tested cell lines (GI₅₀ 25.0⿿44.0 μg/mL). Among the fractions, the greatest activity was exhibited by fraction A (eluted with hexane), which inhibited the growth of all tested cell lines with GI₅₀ of 3.9⿿19.5 μg/mL. Compounds 1 and 4 were the most active, inhibiting the growth of U251, MCF-7, NCI-ADR/RES, 786.0, NCI-H460, PC-3, OVCAR-03 and HaCat cell lines with GI₅₀ < 10 μM. Compound 2 showed moderate activity against MCF-7, NCI-H460, OVCAR-03, K562 and HaCat, with GI₅₀ varying 19.9⿿29.3 μM.     

Design,synthesis and biological activities of sorafenib derivatives as antitumor agents

A series of novel sorafenib derivatives, 9a–w, was designed and synthesized in high yields using various substituted anilines, and their antiproliferative activities against HCT116, PC-3 and MDA-MB-231 cell lines were also evaluated and described. All compounds exhibited potent antiproliferative activity against HCT116 and PC-3 cells with IC₅₀ = 2.8–52.0 and 2.2–45.6 μM; compounds 9p and 9q demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines, the cytotoxicity of compound 9r is more potent than that of sorafenib. Compounds (9g, 9p, 9q and 9r) were chosen for further evaluation of the anti-angiogenesis activity, and showed the inhibition of sprout formation from aortic ring ex vivo. The structures of all the newly synthesized compounds were determined by ¹H NMR, ¹³C NMR and HRMS.     

Isolation of antiplasmodial anthraquinones from Kniphofia ensifolia,and synthesis and structure–activity relationships of related compounds

Bioassay-guided separation of the South African plant Kniphofia ensifolia for antiplasmodial activity led to the isolation of two new anthraquinones, named kniphofiones A and B (3 and 4), together with three known bioactive anthraquinone monomers (1, 2 and 5), and four known bisanthraquinones (6–9). The structures of the two new compounds were elucidated based on analyses of their 1D and 2D NMR spectra and mass spectrometric data. The dimeric compounds 6 and 7 displayed the strongest antiplasmodial activity among all the isolated compounds, with IC₅₀ values of 0.4 ± 0.1 and 0.2 ± 0.1 μM, respectively. The two new compounds displayed modest activities, with IC₅₀ values of 26 ± 4 and 9 ± 1 μM, respectively. Due to the synthetic accessibility of the new compounds and the increased activity shown by the dimeric compounds, a structure–activity relationship study was conducted. As a result, one analogue of kniphofione B (4), the caffeic acid derivative of aloe-emodin, was found to have the highest activity among all the aloe-emodin derivatives, with an IC₅₀ value of 1.3 ± 0.2 μM.     

Tirucallane triterpenoids from the stem bark of Araliopsis synopsis

Two new tirucallane triterpenoids, 21-methoxy-21,23-epoxy-tirucalla-7,24-dien-3α-ol (1) and 21-methoxy-21,23-epoxy-tirucalla-7,24-diene-1α,3α-diol (2), together with thirteen known compounds were isolated from the CH₂Cl₂ extract of the stem bark of Araliopsis synopsis. The structures of the compounds were determined by comprehensive analyses of their 1D and 2D NMR, mass spectral (EI and ESI) data and comparison with previously known analogs. Compounds 1–10 were tested against bacteria, fungi and plant pathogen oomycetes by the paper disk agar diffusion assay resulting in missing to low activities corresponding with MICs > 1 mg/mL. However, compounds 5–10 exhibited high cytotoxic activity against the human Caucasian prostate adenocarcinoma cell PC-3 line, with IC₅₀ 8.5–12.5 μM compared to the standard Doxorubicin with IC₅₀ = 0.9 μM, while compounds 1, 3 and 4 showed low activity.