Design,synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC₅₀ values in range of 3.42–8.05?μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.     

Antiproliferative activity and apoptosis inducing effects of nitric oxide donating derivatives of evodiamine

The first series of nitric oxide donating derivatives of evodiamine were designed and prepared. NO releasing ability of all target derivatives was evaluated in BGC-823, Bel-7402 and L-02 cells. The cytotoxicity was evaluated against three human tumor cell lines (Bel-7402, A549 and BGC-823) and normal human liver cells L-02. The nitrate derivatives 11a and 11b only exhibited moderate activity and furoxan-based derivatives 13a–c, 14a and 14b showed promising activity. 13c showed good cytotoxic selectivity between tumor and normal liver cells and was further investigated for its apoptotic properties on human hepatocarcinoma Bel-7402 cells. The molecular mode of action revealed that 13c caused cell-cycle arrest at S phase and induced apoptosis in Bel-7402 cells through mitochondria-related caspase-dependent pathways.     

Synthesis and biological evaluation of 2,4-disubstituted phthalazinones as Aurora kinase inhibitors

A series of 2,4-disubstituted phthalazinones were synthesized and their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects were evaluated. Among them, N-cyclohexyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-1-oxophthalazin-2(1H)-yl) methyl) benzamide (12c) exhibited the most potent antiproliferation against five carcinoma cell lines (HeLa, A549, HepG2, LoVo and HCT116 cells) with IC₅₀ values in range of 2.2–4.6?μM, while the IC₅₀ value of reference compound VX-680 was 8.5–15.3?μM. Moreover, Aurora kinase assays exhibited that compound 12c was potent inhibitor of AurA and AurB kinase with the IC₅₀ values were 118?±?8.1 and 80?±?4.2?nM, respectively. Molecular docking studies indicated that compound 12c forms better interaction with both AurA and AurB. Furthermore, compound 12c induced G2/M cell cycle arrest in HeLa cells by regulating protein levels of cyclinB1 and cdc2. These results suggested that 12c is a promising pan-Aurora kinase inhibitor for the potential treatment of cancer.     

Synthesis and antiproliferative evaluation of 6-arylindeno[1,2-c]quinoline derivatives

A number of 6-arylindeno[1,2-c]quinoline derivatives were synthesized and evaluated for their antiproliferative activities against the growth of five cancer cell lines including human hepatocelluar carcinoma (Hep G2, Hep 3B and Hep2.2.1), non-small cell lung cancer (A549 and H1299), and normal diploid embryonic lung cell line (MRC-5). The preliminary results indicated that 9-(3-(dimethylamino)propoxy)-6-(4-(3-(dimethylamino)propoxy)phenyl)-2-fluoro-11H-indeno[1,2-c]quinolin-11-one (14c) was the most potent with GI₅₀ values of 0.61, 0.67, 0.59, and 0.72 μM against the growth of Hep G2, Hep 3B, Hep 2.2.1, and H1299 cells, respectively. Results have also shown that 2,9-bis(3-(dimethylamino)propoxy)-6-(4-(3-(dimethylamino)propoxy)phenyl)-11H-indeno[1,2-c]quinolin-11-one (17), which exhibited GI₅₀ of 0.60 and 0.68 μM against the growth of Hep G2 and A549, respectively, was more active than the positive topotecan and irinotecan. Compound 17 was less toxic than topotecan against the growth of normal cell (MRC-5) and therefore, was selected for further evaluation. Results indicated that compound 17 induce cell cycle arrest in G2/M phase, DNA fragmentation, and disrupt the microtubule network in A549 cells. The apoptotic induction may through the cleavage of PARP.     

Design,synthesis and biological evaluation of artemisinin derivatives containing fluorine atoms as anticancer agents

Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by ¹H NMR, ¹³C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC₅₀?=?2.1?μM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation.     

In vitro cytotoxicity on human ovarian cancer cells by T-type calcium channel blockers

The growth inhibition of human cancer cells via T-type Ca²⁺ channel blockade has been well known. Herein, a series of new 3,4-dihydroquinazoline derivatives were synthesized via a brief SAR study on KYS05090 template and evaluated for both T-type Ca²⁺ channel (Ca_v3.1) blockade and cytotoxicity on three human ovarian cancer cells (SK-OV-3, A2780 and A2780-T). Most of compounds except 6i generally exhibited more potent cytotoxicity on SK-OV-3 than mibefradil as a positive control regardless of the degree of T-type channel blockade. In particular, eight compounds (KYS05090, 6a and 6c–6h) showing strong channel blockade exhibited almost equal and more potent cytotoxicity on A2780 when compared to mibefradil. On A2780-T paclitaxel-resistant human ovarian carcinoma, two compounds (KYS05090 and 6d) were 20-fold more active than mibefradil. With respect to cell cycle arrest effect on A2780 and A2780-T cells, KYS05090 induced large proportion of sub-G₁ phase in the cell cycle progression of A2780 and A2780-T, meaning the induction of cancer cell death instead of cell cycle arrest via blocking T-type Ca²⁺ channel. Among new analogues, compounds 6g and 6h induced cell cycle arrest at G₁ phase of A2780 and A2780-T cells in dose-dependent manner and exhibited strong anti-proliferation effects of ovarian cancer cells by blocking T-type Ca²⁺ channel. Furthermore, 6g and 6h possessing strong cytotoxic effects could induce apoptosis of A2780 cells, which was detected by confocal micrographs using DAPI staining.     

Artemisinin-indole and artemisinin-imidazole hybrids: Synthesis,cytotoxic evaluation and reversal effects on multidrug resistance in MCF-7/ADR cells

A series of artemisinin derivatives with MDR reversal activity were designed and synthesized. All hybrids were screened to anticancer activities against four human cancer cell lines (A549, MCF-7, HepG-2, MDA-MB-231) and normal human hepatic cell (L02) in vitro. Most of the new compounds showed higher anticancer activities than artemisinin, among which compounds 11a and 11c displayed superior potency with IC₅₀ 6.78?μM and 5.25?μM against MCF-7, respectively. The further research indicated that the most potent 11c induced cell cycle arrest at G2 phase in MCF-7. Additionally, compound 11c showed remarkable MDR reversal activity which reversed adriamycin against MCF-7/ADR cells with IC₅₀ 0.76?μM.     

Synthesis and biological evaluation of 4β-(thiazol-2-yl)amino-4′-O-demethyl-4-deoxypodophyllotoxins as topoisomerase-II inhibitors

A series of 4β-(thiazol-2-yl)amino-4′-O-demethyl-4-deoxypodophyllotoxins were synthesized, and their cytotoxicities were evaluated against four human cancer cell lines (A549, HepG2, HeLa, and LOVO cells) and normal human diploid fibroblast line WI-38. Some of the compounds exhibited promising antitumor activity and less toxicity than the anticancer drug etoposide. Among them, compounds 15 and 17 were found to be the most potent synthetic derivatives as topo-II inhibitors, and induced DNA double-strand breaks via the p73/ATM pathway as well as the H2AX phosphorylation in A549 cells. These compounds also arrested A549 cells cycle in G2/M phase by regulating cyclinB1/cdc2(p34). Taken together, these results show that a series of compounds are potential anticancer agents.     

Synthesis,characterization and Akt phosphorylation inhibitory activity of cyclopentanecarboxylate-substituted alkylphosphocholines

Akt is activated in most human cancers and contributes to cell growth, proliferation and cellular survival pathway. Accordingly, it is an attractive target for anticancer therapy. A series of novel alkylphosphocholines, incorporating cyclopentanecarboxylate in the phospholipid head group with trans and cis orientations, were synthesized and evaluated for their Akt phosphorylation inhibitory activities and cytotoxicities against human cancer cell lines, A549, MCF-7 and KATO III. Among the synthesized compounds, 5a, 5b and 6c exhibited potent inhibitory Akt phosphorylation effects with IC₅₀ value of 3.1, 2.0 and 3.0 μM, respectively, and their potencies were better than those of three reference compounds miltefosine, perifosine and edelfosine. All the new compounds, except 5d and 6e, displayed more potent growth inhibition against A549 cells than reference compounds. Specifically, compound 5b exhibited most remarkable cytotoxicities on A549 cells as well as MCF-7 and KATO III cells. Importantly, the cytotoxic effects of these compounds correlated with their Akt phosphorylation inhibitory activities.     

Synthesis and biological evaluation of new bisindole-imidazopyridine hybrids as apoptosis inducers

A series of diindolylmethanes (5a-t) were designed, synthesized, and examined for their cytotoxicity against four human cancer cell lines like prostate (DU-145), lung (A549), breast (MCF-7) and cervical cancer (HeLa). These results revealed that among all the hybrids, two (5k and 5r) were identified and exhibited significant cytotoxic effect against A549 cancer cells with IC₅₀ values of 1.65 ± 0.3 and 1.80 ± 0.8 µM respectively. To investigate the reasons for the cytotoxic activity, the conventional biological assays were carried out with 5k and 5r on the A549 cancer cells. Both hybrids led to the arrest of A549 cell lines at the G2/M phase of the cell cycle and strongly induced apoptosis. Further the apoptotic effects of 5k and 5r were confirmed by ROS, annexin-V FITC, and mitochondrial membrane potential. Moreover, structure–activity relationships were elucidated with various substitutions on these hybrids.     

Synthesis,antioxidant and antiproliferative activities of 1,3,4-thiadiazoles derived from phenolic acids

Two 2-amino-1,3,4-thiadiazoles containing phenolic hydroxyl groups were combined with different carboxylic acid chlorides giving sixteen amide derivatives with good antioxidant and antiproliferative potential. The compound 3′c with an adamantane ring displayed excellent DPPH radical scavenging activity and good cytotoxic activity against human acute promyelocytic leukemia HL-60 cells, while 1,3,4-thiadiazole 3′h with 4-chlorophenyl moiety was found to be the most effective in inhibition of survival of lung carcinoma A549 cells. All examined thiadiazoles except 3a and 3′a exerted higher cytotoxic activities on A549 and HL-60 cancer cells when compared with normal fibroblasts MRC-5, pointing to selectivity in their antiproliferative action. Some of the most active novel compounds 3c, 3′c, 3′g and 3′h induced significant increase in the percentage of HL-60 cells in the subG1 cell cycle phase in comparison with the control cells. The induction of cell death in HL-60 cells by these compounds was at least partially dependent on activation of caspase-3 and caspase-8. The compounds 3c and 3′c exerted strong antiangiogenic activity. Furthermore, compounds 3c, 3′c, 3′g and 3′h showed the ability to down-regulate the MMP2 and VEGFA expression levels in the treated HL-60 cells when compared with the control cell samples.     

Design and synthesis of 4β-Acetamidobenzofuranone-podophyllotoxin hybrids and their anti-cancer evaluation

A new series of amide derivatives of 4β-Acetamidobenzofuranone-podophyllotoxin hybrids (14a–g) were synthesized and their chemical structures were confirmed by ¹H, ¹³C NMR and mass spectral data. Further, all the synthesized Acetamidobenzofuranone-podophyllotoxin hybrids were evaluated for in vitro cytotoxic activity against a panel of four human cancer cell lines i.e., human breast (MCF-7, MDA MB-231), lung (A549), and prostrate (DU-145). Among benzofuranone-podophyllotoxin hybrid compounds, 14b and 14e were exhibited more potent activity than standard drug and 14c and 14f were showed anticancer activity equivalent to etoposide.     

One-pot synthesis and biological evaluation of N-(aminosulfonyl)-4-podophyllotoxin carbamates as potential anticancer agents

A series of N-(aminosulfonyl)-4-podophyllotoxin carbamates were synthesized via the Burgess-type intermediate, and their antiproliferative activities were evaluated. Most of them possessed more potent cytotoxic effects against four human tumor cell lines (HeLa, A-549, HCT-8 and HepG2) and less toxic to normal human fetal lung fibroblast WI-38 cells than etoposide. In particular, N-(morpholinosulfonyl)-4-podophyllotoxin carbamate (9) exhibited the most potent activity towards these four tumor cells with IC₅₀ values in the range of 0.5–16.5 μM. Furthermore, immunofluorescence analysis revealed that 9 induced cell apoptosis by up-regulating the expression of p53 and ROS. Meanwhile, 9 effectively inhibited tubulin polymerization and microtubule assembly at cellular levels in HeLa cells. In addition, 9 could induce cell cycle arrest in the G2/M phase in HeLa cells by up-regulating levels of cyclinB1 and cdc2 and decreasing the expression of p-cdc2. These results indicated that 9 had potential for further development as anticancer agents.     

Syntheses, characterization and antitumor activities of transition metal complexes with isoflavone

Five new complexes were synthesized by the reaction of 4′-methoxy-5,7-dihydroxy-isoflavone ligand (a) with transition metal ions zinc (Zn²⁺) (complex b), manganese (Mn²⁺) (complex c), copper (Cu²⁺) (complex d), cobalt (Co²⁺) (complex e) and nickel (Ni²⁺) (complex f). The composition of the complexes has been characterized by elemental analysis, IR, mass spectrometry (MS) and ¹H NMR spectrometric techniques. Their antitumor properties were evaluated against five human cancer cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. The results indicated that the complexes possess higher growth inhibitory effects than free isoflavone and corresponding metal ions. Complex c and f showed greater antitumor activity and selectivity than other described complexes, even more effective than the positive control cisplatin against the selected cell lines. In addition, DNA flow cytometric analysis demonstrated that complexes display a significant G₂/M phase arrest, which then progressed to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI).     

Synthesis and an angiolytic role of novel piperazine–benzothiazole analogues on neovascularization,a chief tumoral parameter in neoplastic development

A novel series of benzoic acid N′-[2-(4-benzothiazol-2-yl-piperazin-1-yl)-acetyl]-hydrazides 6a–j were synthesized and characterized by IR, ¹H, ¹³C NMR, elemental and mass spectral analyses. The in-vitro cytotoxicity and cell viability assay of the synthesized compounds 6a–j were evaluated against Dalton’s lymphoma ascites (DLA) cells. Our results showed that compound 6c with a bromo group on phenyl ring has showed promising antiproliferative efficacy. Further investigation of compound 6c on in-vivo treatment model depicts the increased tumor suppression through inhibition of angiogenesis.     

Discovery of thiapyran-pyrimidine derivatives as potential EGFR inhibitors

A series of novel thiapyran-pyrimidine derivatives (10a–10h, 11a–11g, 12a–12f, 13a–13f, 14a–14f) were synthesized and their antiproliferative activities were tested. Most of the target compounds showed good activity on one or more cancer cell lines but low activity on human normal cell LO2. The most promising compound 13a exhibited the similar IC₅₀ values on A549 and H1975 cell lines to the lead drug Olmutinib, and exhibited excellent activity and selectivity on EGFR^T790M/L858R in the kinase experiment. AO and Hoechst33258 staining indicated that 13a could effectively induce H1975 cells apoptosis. Cell cycle and apoptosis analysis suggested that 13a could block cancer cells in G2/M phase and induce into late apoptosis in a manner of concentration-dependent. The structure–activity relationship of 13a was analyzed to explore its mechanism. All the results showed that 13a was a promising EGFR inhibitor.     

Synthesis and antitumor activities of novel α-aminophosphonates dehydroabietic acid derivatives

A series of novel α-aminophosphonate derivatives containing DHA structure were designed and synthesized as antitumor agents. In vitro antitumor activities of these compounds against the NCI-H460 (human lung cancer cell), A549 (human lung adenocarcinoma cell), HepG2 (human liver cancer cell) and SKOV3 (human ovarian cancer cell) human cancer cell lines were evaluated and compared with commercial anticancer drug 5-fluorouracil (5-FU), employing standard MTT assay. The pharmacological screening results revealed that many compounds exhibited moderate to high levels of antitumor activities against the tested cancer cell lines and that most demonstrated more potent inhibitory activities compared with the commercial anticancer drug 5-FU. The action mechanism of representative compound 7c was preliminarily investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which indicated that the compound can induce cell apoptosis in NCI-H460 cells. Cell cycle analysis showed that compound 7c mainly arrested NCI-H460 cells in G1 stage.     

Investigation of chemical constituents from Spiraea prunifolia var. simpliciflora and their biological activities

Quantum mechanics (QM)-based calculations for elucidating full structures of natural compounds are growing in importance and reliability. Two new phenolic glycosides (1 and 2) and 11 known compounds were isolated from the twigs of Spiraea prunifolia var. simpliciflora. The chemical structures of the new compounds (1 and 2) were initially established through different NMR techniques (¹H and ¹³C NMR, COSY, HSQC, and HMBC), HRMS data analysis, and chemical hydrolysis. These structure assignments were further verified by QM-based NMR chemical shift calculations. All of the purified compounds (1–13) were evaluated for their cytotoxicity against four human cancer cell lines (A549, SK-OV-3, SK-MEL-2, and BT549). Those phytochemicals were also evaluated for both anti-inflammatory activity through the measurement of nitric oxide (NO) production levels in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cell lines and neuroprotective effects via induction of nerve growth factor (NGF) in C6 glioma cells.     

Some new indole–coumarin hybrids; Synthesis,anticancer and Bcl-2 docking studies

Hybrid molecules have attracted attention for their improved biological activity, selectivity and lesser side effects profile, distinct from their individual components. In the quest for novel anticancer drug entities, three series of indole–coumarin hybrids – 3-(1-benzyl-1H-indol-2-yl)-2H-chromen-2-ones, 2-(2-oxo-2H-chromen-3-yl)-1H-indole-3-carbaldehydes and 2-(2-oxo-2H-chromen-3-yl)-1H-indole-3-carboxylic acids were synthesized. All the synthesized compounds were characterized by spectral techniques like IR, ¹H NMR, ¹³C NMR, mass spectrometry and elemental analysis. In silico docking studies of synthesized molecules with apoptosis related gene Bcl-2 that is recognized to play an important role in tumerogenesis were carried out. Dose-dependent cytotoxic effect of the compounds in human breast adenocarcinoma (MCF-7) and normal cell lines were assessed using MTT assay and compared with that of the standard marketed drug, Vincristine. Compound 4c had a highly lipophilic bromine substituent capable of forming halogen bond and was identified as a potent molecule both in docking as well as cytotoxicity studies. Flow cytometric cell cycle analysis of 4c exhibited apoptotic mode of cell death due to cell cycle arrest in G2/M phase. Structure activity relationship of these hybrid molecules was also studied to determine the effect of steric and electronic properties of the substituents on cell viability.