Bradykinin antagonists and thiazolidinone derivatives as new potential anti-cancer compounds

Glioblastoma (GB), the most aggressive brain tumour, and mantle cell lymphoma (MCL), a rare but very aggressive type of lymphoma, are highly resistant to chemotherapy. GB and MCL chemotherapy gives very modest results, the vast majority of patients experience recurrent disease. To find out the new treatment modality for drug-resistant GB and MCL cells, combining of bradykinin (BK) antagonists with conventional temozolomide (TMZ) treatment, and screening of thiazolidinones derivatives were the main objectives of this work. As it was revealed here, BKM-570 was the lead compound among BK antagonists under investigation (IC₅₀ was 3.3 μM) in human GB cells. It strongly suppressed extracellular signal-regulated kinases 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation. BK antagonists did not decrease the viability of MCL cells, thus showing the cell-specific mode, while thiazolidinone derivatives, a novel group of promising anti-tumour compounds inhibited proliferation of MCL cells: IC₅₀ of ID 4526 and ID 4527 compounds were 0.27 μM and 0.16 μM, correspondingly. However, single agents are often not effective in clinic due to activation of collateral pathways in tumour cells. We demonstrated a strong synergistic effect after combinatorial treatment by BKM-570 together with TMZ that drastically increased cytotoxic action of this drug in rat and human glioma cells. Small proportion of cells was still viable after such treatment that could be explained by presence of TMZ-resistant cells in the population.It is possible to expect that the combined therapy aimed simultaneously at different elements of tumourigenesis will be more effective with lower drug concentrations than the first-line drug temozolomide used alone in clinics.     

The first total synthesis and biological evaluation of marine natural products ma’edamines A and B

We have developed the first total syntheses of marine natural products ma’edamines A (18) and B (20). Structurally, they contain a pyrazine-2-(1H)-one core and were screened for antiproliferative activity on several cancer cell lines. Out of the six cell lines tested, ma’edamines A and B showed significant cytotoxicity against human colon cancer line COLO 205 (IC₅₀ 7.9 and 10.3 μM, respectively), breast cancer cell line MCF-7 (IC₅₀: 6.9 and 10.5 μM, respectively) and human lung adenocarcinoma cell line A549 (IC₅₀: 12.2 and 15.4 μM, respectively). The apoptotic effect of ma’edamines was confirmed by comet assay. Hence ma’edamines are likely to be useful as leads for development of a new class of anti-cancer agents.     

Novel fluorine‐containing chiral hydrazide‐hydrazones: Design,synthesis, structural elucidation,antioxidant and anticholinesterase activity,and in silico studies

In this study, a series of fluorine‐containing chiral hydrazide‐hydrazone derivatives [III‐XII] from ?‐cysteine ethyl ester hydrochloride was synthesized as new antioxidant and anticholinesterase agents. The antioxidant activity of these derivatives was evaluated by ABTS^+· and DPPH^· scavenging and CUPRAC assays and the anticholinesterase activity by the Ellman method spectrophotometrically. The results of the antioxidant assay showed that compounds V , IX , and X exhibited higher activity than BHT and α‐tocopherol used as positive standards. Among the synthesized derivatives, compound IX (IC₅₀: 2.3 ± 1.6 μM) exhibited higher acetylcholinesterase inhibitory activity than galantamine (IC₅₀: 4.5 ± 0.8 μM). Compounds XI (IC₅₀: 9.6 ± 1.0 μM), IX (IC₅₀: 12.5 ± 1.6 μM), III (IC₅₀: 16.0 ± 1.6 μM), X (IC₅₀: 17.2 ± 1.8 μM), VI (IC₅₀: 20.2 ± 0.8 μM), XII (IC₅₀: 21.5 ± 1.0 μM), and VII (IC₅₀: 24.6 ± 0.6 μM) displayed better butyrylcholinesterase inhibitory activity than galantamine (IC₅₀: 46.03 ± 0.14 μM). ADME‐Tox analysis was used to probe the drug‐like properties of the compounds. Molecular docking studies were also applied to understand the interactions between compounds and targets. The docking calculations were supported by the experimental data. In particular, compound IX , having better activity than galantamine against acetylcholinesterase and butyrylcholinesterase enzymes, was visualized using molecular docking.     

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.     

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.     

Design,synthesis and biological evaluation of indeno[1,2-d]thiazole derivatives as potent histone deacetylase inhibitors

Novel indeno[1,2-d]thiazole hydroxamic acids were designed, synthesized, and evaluated for histone deacetylases (HDACs) inhibition and antiproliferative activities on tumor cell lines. Most of the tested compounds exhibited HDAC inhibition and antiproliferative activity against both MCF7 and HCT116 cells with GI₅₀ values in the sub-micromolar range. Among them, compound 6o showed good inhibitory activity against pan-HDAC with IC₅₀ value of 0.14 μM and significant growth inhibition on MCF7 and HCT116 cells with GI₅₀ values of 0.869 and 0.535 μM, respectively.     

Design,synthesis and biological evaluation of (E)-3-(3,4-dihydroxyphenyl)acrylylpiperazine derivatives as a new class of tubulin polymerization inhibitors

A series of novel (E)-3-(3,4-dihydroxyphenyl)acrylylpiperazine derivatives had been synthesized and evaluated their biological activities as potential tubulin polymerization inhibitors. Among these compounds, compound 3q exhibited potent antiproliferative activities against three cancer cell lines in vitro, and antitubulin polymerization activity with IC₅₀ of 0.92 μM, which was superior to that of colchicine (IC₅₀ = 1.34 μM). Docking simulation was performed to insert compound 3q into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. These results suggested that compound 3q may be a promising antitubulin agent for the potential treatment of cancer.     

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.     

Structure–activity relationship study of 4-(thiazol-5-yl)benzoic acid derivatives as potent protein kinase CK2 inhibitors

Two classes of modified analogs of 4-(thiazol-5-yl)benzoic acid-type CK2 inhibitors were designed. The azabenzene analogs, pyridine- and pyridazine-carboxylic acid derivatives, showed potent protein kinase CK2 inhibitory activities [IC₅₀ (CK2α) = 0.014–0.017 μM; IC₅₀ (CK2α′) = 0.0046–0.010 μM]. Introduction of a 2-halo- or 2-methoxy-benzyloxy group at the 3-position of the benzoic acid moiety maintained the potent CK2 inhibitory activities [IC₅₀ (CK2α) = 0.014–0.016 μM; IC₅₀ (CK2α′) = 0.0088–0.014 μM] and led to antiproliferative activities [CC₅₀ (A549) = 1.5–3.3 μM] three to six times higher than those of the parent compound.     

Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity

Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR–TK inhibitory activity. Especially, N⁶-((5-bromothiophen-2-yl)methyl)-N⁴-(3-chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC₅₀ = 3.11 μM for Hep G2, IC₅₀ = 0.82 μM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells.     

Hirtellanines A and B,a pair of isomeric isoflavonoid derivatives from Campylotropis hirtella and their immunosuppressive activities

A pair of isomeric isoflavonoid derivatives, Hirtellanines A (1) and B (2), has been isolated from the roots of Campylotropis hirtella (Franch.) Schindl. and their structures were elucidated on the basis of spectroscopic methods, with special emphasis on 1D and 2D NMR techniques. The in vitro assay showed that Hirtellanine A had strong B lymphocyte suppression activity (IC₅₀: 0.06 μM) and T lymphocyte suppression activity (IC₅₀: 0.92 μM). Hirtellanine B showed moderate B lymphocyte suppression activity (IC₅₀: 3.00 μM) and T lymphocyte suppression activity (IC₅₀: 9.55 μM). Due to the potent immunosuppressive activities and lower cytotoxicity, Hirtellanine A could be a promising lead towards novel immunosuppressive agents.     

Synthesis and antiproliferative activity of two diastereomeric lignan amides serving as dimeric caffeic acid-l-DOPA hybrids

Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl₃-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256 μM and periods of treatment of 24, 48 and 72 h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC₅₀ 64–70 μM) for the MDA-MB-231 cell line after 24–48 h of treatment, but they were more selective and much more potent (IC₅₀ 4–16 μM) for the MCF-7 cells after 48 h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72 h of treatment (IC₅₀ 1–2 μM), probably as the result of slow hydrolysis of their methyl ester functions.     

Synthesis,biological evaluation, 3D-QSAR studies of novel aryl-2H-pyrazole derivatives as telomerase inhibitors

A series of novel aryl-2H-pyrazole derivatives bearing 1,4-benzodioxan or 1,3-benzodioxole moiety were designed as potential telomerase inhibitors to enhance the ability of aryl-2H-pyrazole derivatives to inhibit telomerase, a target of anticancer. The telomerase inhibition tests showed that compound 16A displayed the most potent inhibitory activity with IC₅₀ value of 0.9 μM for telomerase. The antiproliferative tests showed that compound 16A exhibited high activity against human gastric cancer cell SGC-7901 and human melanoma cell B16-F10 with IC₅₀ values of 18.07 and 5.34 μM, respectively. Docking simulation showed that compound 16A could bind well with the telomerase active site and act as telomerase inhibitor. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent telomerase inhibitory activity.     

Evaluation of Mongolian compound library for potential antimalarial and anti-Toxoplasma agents

179 compounds in a Mongolian compound library were investigated for their inhibitory effect on the in vitro growth of Plasmodium falciparum and Toxoplasma gondii. Among these compounds, brachangobinan A at a half-maximal inhibition concentration (IC₅₀) of 2.62 μM and a selectivity index (SI) of 27.91; 2-(2′-hydroxy-5′-O-methylphenyl)-5-(2″,5″-dihydroxyphenyl)oxazole (IC₅₀ 3.58 μM and SI 24.66); chrysosplenetin (IC₅₀ 3.78 μM and SI 15.26); 4,11-di-O-galloylbergenin (IC₅₀ 3.87 μM and SI 13.38); and 2-(2′,5′-dihydroxyphenyl)-5-(2″-hydroxyphenyl)oxazole (IC₅₀ 6.94 μM and SI 11.48) were identified as potential inhibitors of P. falciparum multiplication. Additionally, tricin (IC₅₀ 12.94 μM and SI > 23.40) was identified as a potential inhibitor of T. gondii multiplication. Our findings represent a good starting point for developing novel antimalarial and anti-Toxoplasma therapeutics from Mongolian compounds.     

Triazoxins: Novel nucleosides with anti-Giardia activity

Novel nucleoside analogues named “triazoxins” were synthesized. Of these, two analogues were found to be highly effective against Giardia lamblia, an intestinal parasite and a major cause of waterborne infection, worldwide. While compound 7 reduced the growth of trophozoites in culture (IC₅₀, ~5 μM), compound 21 blocked the in vitro cyst production (IC₅₀ ~5 μM). Compound 21 was also effective against trophozoites (IC₅₀, ~36 μM). A third analogue (compound 8) was effective against both trophozoites (IC₅₀, ~36 μM) and cysts (IC₅₀, ~20 μM) although at higher concentration. Thus triazoxin analogues are unique and exhibit morphology (i.e., trohozoites or cysts) -specific effects against Giardia.     

Identification of novel acetylcholinesterase inhibitors: Indolopyrazoline derivatives and molecular docking studies

The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC₅₀: 0.68 ± 0.13 μM) with strong DPPH and ABTS radical scavenging activity (IC₅₀: 13.77 ± 0.25 μM and IC₅₀: 12.59 ± 0.21 μM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC₅₀: 0.74 ± 0.09 μM) and with DPPH and ABTS radical scavenging activity (IC₅₀: 13.52 ± 0.62 μM and IC₅₀: 13.13 ± 0.85 μM), respectively. Finally, molecular docking studies provided prospective evidence to identify key interactions between the active inhibitors and the AChE that furthermore led us to the identification of plausible binding mode of novel indolopyrazoline derivatives. Additionally, in-silico ADME prediction using QikProp shows that these derivatives fulfilled all the properties of CNS acting drugs. This study confirms the first time reporting of indolopyrazoline derivatives as potential anti-Alzheimer agents.     

Design,synthesis and apoptosis-related antiproliferative activities of chelidonine derivatives

To get chelidonine derivatives with enhanced antiproliferative activity and selectivity, a series of nitric oxide donating derivatives (10a-f and 11a-j) were designed, synthesized and biologically evaluated. Compared with chelidonine, these compounds exhibited lower IC₅₀ values against human hepatoma cells HepG2, breast cancer cells MCF-7, colon cancer cells HCT-116, as well as leukemia cells K562. Compound 11j displayed the strongest antiproliferative activity with IC₅₀ values of 3.91, 6.90, 4.36 and 1.12 μM against the above four cells, respectively. Nevertheless, it showed an IC₅₀ value >40 μM against human peripheral blood mononuclear cells (PBMCs), which demonstrated high selectivity between normal and cancer blood cells. In further mechanism studies, 11j showed the capability to induce K562 cells apoptosis, S phase cell cycle arrest and mitochondrial membrane potential disorder. Besides, 11j was found to be effective in promoting the expression of proapoptotic protein Bad and suppressing the expression of anti-apoptotic proteins Bcl-xL, catalase, survivin, claspin and clusterin.     

Design,synthesis, and biological evaluation of novel aminopyrimidinylisoindolines as AXL kinase inhibitors

A novel series of aminopyrimidinylisoindoline derivatives 1a-w having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC₅₀ values of submicromolar range. Especially, compound 1u possessing (4-acetylpiperazin-1-yl)phenyl moiety exhibited extremely excellent efficacy (IC₅₀?=?<0.00050?μM). Their in vitro antiproliferative activities were tested over five cancer cell lines. Most compounds showed good antiproliferative activities against HeLa cell line. The kinase panel profiling of 50 different kinases and the selected inhibitory activities for the representative compound 1u were carried out. The compound 1u exhibited excellent inhibitory activities (IC₅₀?=?<0.00050, 0.025, and 0.050?μM for AXL, MER, and TYRO3, respectively) against TAM family, together with potent antiproliferative activity against MV4-11 cell line (GI₅₀?=?0.10?μM) related to acute myeloid leukemia (AML).     

Synthesis and biological evaluation of pyrazole derivatives containing thiourea skeleton as anticancer agents

Two series of pyrazole derivatives designing for potential EGFR kinase inhibitors have been discovered. Some of them exhibited significant EGFR inhibitory activity. Compound 3-(3,4-dimethylphenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (C5) displayed the most potent EGFR inhibitory activity with IC₅₀ of 0.07 μM, which was comparable to the positive control erlotinib. Docking simulation was performed to position compound C5 into the EGFR active site to determine the probable binding model. Antiproliferative assay results indicating that some of the pyrazole derivatives own high antiproliferative activity against MCF-7. Compound C5 showed significant antiproliferative activity against MCF-7 with IC₅₀ of 0.08 μM. Therefore, compound C5 with potent inhibitory activity in tumor growth inhibition would be a potential anticancer agent.     

In vitro inhibitory effects of ethanol extract of Danshen (Salvia miltiorrhiza) and its components on the catalytic activity of soluble epoxide hydrolase

Background: Soluble epoxide hydrolase (sEH) has been demonstrated to be a key enzyme involved in the pathologic development of several cardiovascular diseases and inflammation, and inhibition of sEH is therefore very helpful or crucial for the treatment of ischemia-reperfusion injury, cardiac hypertrophy, hypertension and inflammation. Danshen, the dried root of Salvia miltiorrhiza (Fam. Labiatae), has been used for the treatment of cardiovascular and cerebrovascular diseases in China and other countries for hundreds of years. Recent studies indicated that Danshen and its preparations also have potential for the management of inflammation. However, little information is available about the possibility of Danshen and its components on sEH inhibition.Purpose and methods: Danshen extracts and its constituents were tested for sEH inhibition using its physiological substrate, 8,9-EET, based on a LC–MS/MS assay in this study.Results: Among the tested 15 compounds, tanshinone IIA and cryptotanshinone were found to be the potent (K_i = 0.87 μM) and medium (K_i = 6.7 μM) mixed-type inhibitors of sEH, respectively. Salvianolic acid C (K_i = 8.6 μM) was proved to be a moderate noncompetitive sEH inhibitor. In consistent with the inhibition results of the pure compounds, the 75% ethanol extract of Danshen (EE, IC₅₀ = 86.5 μg/ml) which contained more tanshinone IIA and cryptotanshinone exhibited more potent inhibition on sEH than the water extract (WE, IC₅₀ > 200 μg/ml) or 1 M NaHCO₃ (BE, IC₅₀ > 200 μg/ml) extract.Conclusion: These data indicated that using the ethanol fraction of Danshen and increasing the amounts of tanshinone IIA, cryptotanshinone and salvianolic acid C, especially the contents of tanshinone IIA in Danshen extract or preparations to enhance the inhibitory effects on sEH might be efficient ways to improve its cardiovascular protective and anti-inflammatory effects, and that herbal medicines could be an untapped reservoir for sEH-inhibition agents and developing sEH inhibitors from the cardiovascular protective and anti-inflammatory herbs is a promising approach.