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 cytotoxicity evaluation of oleanolic acid derivatives

Twelve derivatives of oleanolic acid (1) have been synthesized and evaluated for their inhibitory activities against the growth of prostate PC3, breast MCF-7, lung A549, and gastric BGC-823 cancer cells by MTT assays. Within these series of derivatives, compound 17 exhibited the most potent cytotoxicity against PC3 cell line (IC₅₀ = 0.39 μM) and compound 28 displayed the best activity against A549 cell line (IC₅₀ = 0.22 μM). SAR analysis indicates that H-donor substitution at C-3 position of oleanolic acid may be advantageous for improvement of cytotoxicity against PC3, A549 and MCF-7 cell lines.     

Three new chlorinated phenolic glycosides from Przewalskia tangutica

Three new chlorinated phenolic glycosides, namely przewatangosides A-C (1-3), along with one known compound, globosumoside A (4), were isolated from the whole plants of Przewalskia tangutica. Their structures were unequivocally determined by extensive spectroscopic analysis and chemical method. The cytotoxic activities of the isolated phenolic glycosides (1-4) were evaluated against the five human cancer cell lines A549, MCF-7, SMMC-7721, HepG2 and HL-60. Przewatangoside A (1) exhibited weak cytotoxicity against SMMC-7721 with the IC₅₀ value of 38.1 μM. All the tested compounds were inactive (IC₅₀ > 50 μM) to the normal human hepatocyte cell line (L02).     

Steroidal alkaloids from Solanum erianthum and their anti-breast cancer properties

Two new glycoalkaloids, erianosides A (1) and B (2) along with five known compounds (3–7) were isolated from the leaves of Solanum erianthum. Their structures were elucidated from analyses of spectroscopic data and all isolates were tested for in vitro cytotoxic activity against human breast cancer cell lines (BT-549, MDA-MB-231, T74D, and MCF-7). Solasonine (5) and solamargine (6) were active against the aforementioned four cancer cell lines with IC₅₀ values of 27.26–35.89 and 5.84–10.13 μM, respectively. Erianoside A (1) (T74D: IC₅₀, 56.39 µM) and solasodine (3) (BT-549 and MDA-MB-231: IC₅₀, 59.15 and 75.63 µM, respectively) had moderate cytotoxic effects towards some cell lines in the panel.     

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 anti-proliferative activity of a novel 1,2,3-triazole tethered chalcone acetamide derivatives

A new series of 1,2,3-triazole tethered chalcone acetamide derivatives (7a-c & 8a-r) have been synthesized in excellent yields and their structures were determined by analytical and spectral (FT-IR, ¹H NMR, ¹³C NMR & HRMS) studies. The newly synthesized derivatives were evaluated for their cytotoxic activity against four human cancer cell lines, such as HeLa (Human cervical cancer), A549 (Human alveolar adenocarcinoma), MCF-7 (Human breast adenocarcinoma) and SKNSH (Human brain cancer). Among them, compound 7c exhibited good anti-proliferation activity with HeLa (IC₅₀ 7.41 + 0.8 μM), SKNSH (IC₅₀ 8.68 + 1.1 μM), MCF-7 (IC₅₀ 9.76 + 1.3 μM) and MDA-MB-231, while compounds 7a and 7b showed promising anti-proliferation against above four human cancer cell lines with IC₅₀ 7.95–11.62 μM, respectively, compared with the standard drug Doxorubicin. We explored the probable key active site and binding mode interactions in HDAC8 (PDB ID:3SFH) and EHMT2 (PDB ID:3K5K) proteins. The docking results are complementary to the experimental observations.     

Synthesis and anticancer activity of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety

Herein, we designed and synthesized of a novel series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety (10a–j, 13a–j). All the compounds were evaluated for the IC₅₀ values against five cancer cell lines (A549, PC-3, MCF-7, Hela and HepG2). Seven of the target compounds exhibited moderate to excellent cytotoxicity. For these compounds, we tested their inhibitory activities against mTOR kinase, and four of them were tested their inhibitory activities against PI3Kα kinase in further. The results indicated that the optimized compound 10j showed excellent inhibitory activity and cytotoxicity against mTOR kinase, PI3Kα kinase and five cancer cell lines with IC₅₀ values of 1.1 μM, 0.92 μM and 8.77–14.3 μM. Structure–activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-d]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of chromone moiety at C-6 position with carboxyl were benefit to the antitumor activities.     

Design,synthesis and biological evaluation of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment

A series of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment were designed, synthesized, and evaluated for their biological activity. Most compounds showed effective inhibitory activity against cancer cell lines of A549, HeLa and MCF-7. Among them, the most promising compound 40 showed excellent activity against A549, HeLa and MCF-7 cell lines with IC₅₀ values of 1.03, 1.15 and 2.59 μM, respectively, which was 2.606.95 times more active than that of Golvatinib. The structure-activity relationships (SARs) showed that the introduction of 5-methylpyridazin-3(2H)-one to “5-atom linker” and the modification of the amide with morpholine group were beneficial for enhancing the inhibitory activity of compounds. In addition, the further research on compound 40 mainly include c-Met kinase activity, concentration dependence, apoptosis (acridine orange staining), and molecular docking.     

Two new lignans from Gymnotheca chinensis Decne

Two new lignans, gymnothelignans V (1) and W (2), were isolated from a methanol extraction of Gymnotheca chinensis Decne. Their structures were established on the basis of extensive 1D and 2D NMR spectroscopy. Compound 1 exhibited moderate cytotoxicity against the HCT116, HCT15, A549, MCF-7 and HepG2 cancer cell lines with IC₅₀ values of 45.1 μM, 26.9 μM, 49.6 μM, 30.0 μM and 49.7 μM, respectively. Compound 2 exhibited weak cytotoxicity against the A549 cancer cell line with an IC₅₀ value of 41.3 μM.     

Synthesis,biological evaluation and molecular modeling of 1,3,4-thiadiazol-2-amide derivatives as novel antitubulin agents

A series of 1,3,4-thiadiazol-2-amide derivatives (6a–w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC₅₀ values of 0.03 μM, 0.06 μM and 0.05 μM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC₅₀ = 1.73 μM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.     

Three new labdane diterpenes from Loxocalyx urticifolius

Three new labdane diterpenes, namely loxocalyxin D (1), loxocalyxin E (2) and 13-epiloxocalyxin E (3), were isolated from the whole plants of Loxocalyx urticifolius Hemsl. Their structures were elucidated by extensive spectral analysis and chemical methods. The absolute configuration of loxocalyxin D (1) was confirmed by X-ray crystallographic analysis. The cytotoxic activities of the isolated labdane diterpenes were evaluated against the four human cancer cell lines A549, HepG2, HL-60 and MCF-7. 13-epiloxocalyxin E (3) exhibited selective cytotoxicity against A549 and MCF-7 with the IC₅₀ values of 22.4 and 47.3 μM, respectively.     

Design,synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a–e, 13a–f, 14a–f and 15a–i) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC₅₀ values of 1.04 ± 0.11 μM, 0.02 ± 0.01 μM and 9.11 ± 0.55 μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC₅₀ values: 0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.     

Chemical constituents from Abrus cantoniensis and their cytotoxic effects on cancer cells

Two new compounds named 4-(4-hydroxybenzyl)-isofraxidin (1) and 1''-methoxyl-bavacoumestan B (2), along with five known compounds (3–7) were isolated from the EtOAc-soluble extract of Abrus cantoniensis. Their structures were elucidated with spectroscopic and physico-chemical analyses. All isolates were evaluated for their cytotoxic activities against four cancer cell lines including HepG2, SMMC-7721, A549 and MCF-7. Among them, compounds 1 and 5 exhibited significant cytotoxic activity on the above four cell lines. In particular, 1 showed the potent cytotoxic activity on HepG2 and SMMC-7721 cells with IC₅₀ values of 4.31 ± 0.5 and 3.24 ± 0.9 μM, respectively.     

Synthesis,activity and docking studies of phenylpyrimidine–carboxamide Sorafenib derivatives

Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC₅₀ values of 6.35 ± 0.43 μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC₅₀ values of 3.39 ± 0.37 μM. Structure–activity relationships (SARs) and docking studies indicated that the second series (17a–p) showed more active than the first series (16a–g). What’s more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.     

Synthesis,and docking studies of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (14a–e, 15a–g, 16a–e and 17a–g) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7). Four selected compounds (15e, 16a–b and 17a) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Eleven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC₅₀ values of 0.14 ± 0.08 μM, 0.24 ± 0.07 μM and 0.02 ± 0.01 μM, which were 4.6, 1.6 and 473.5 times more active than Foretinib (0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What’s more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity.     

Aplysinopsin analogs: Synthesis and anti-proliferative activity of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-diones

A series of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-dione (3) analogs structurally related to aplysinopsin, and that incorporate a variety of substituents in both the indole and N-benzyl moieties have been synthesized under microwave irradiation and conventional heating methods These analogs were evaluated for their anti-proliferative activity against MCF-7 and MDA-231 breast cancer cell lines, and A549 and H460 lung cancer cell lines. Two analogs, 3f and 3j had IC₅₀ values of 4.4 and 5.2 μM, respectively, compared to 5-fluorouracil (IC₅₀ = 15.2 μM) against MCF-7 cells.     

New phenylpropanoids with cytotoxic activities from Drypetes hainanensis

Phytochemical investigation on Drypetes hainanensis has resulted in the isolation of three new phenylpropanoids, named drypetesins A–C (1–3). Their structures were elucidated by applying various spectroscopic techniques (NMR, UV, IR, MS, and CD). The antiproliferative activities of these compounds were evaluated in vitro against three cultured cancer cell lines. Those new isolates exhibited potent cytotoxic activities against human hepatoma (HepG2), human breast adenocarcinoma (MCF-7), and human lung carcinoma (A-549) cancer cell lines with IC₅₀ value range 5.6–14.8 μM.     

Novel naphthalimide–amino acid conjugates with flexible leucine moiety as side chain: Design,synthesis and potential antitumor activity

A series of novel naphthalimide derivatives with flexible leucine side chains were designed and synthesized. Their antitumor activities were evaluated against HeLa, A549, P388, HL-60, MCF-7, HCT-8 and A375 cancer cell lines in vitro. The preliminary results showed that most of the derivatives had moderate antitumor activities with the IC₅₀ values of 10^?6–10^?5 M. More importantly, compounds 8a–c exhibited exclusive antitumor activities against MCF-7 cell line. The interaction between compound 8b and BSA was also investigated. DNA binding experiments showed that these derivatives behaved as DNA intercalating agents. This work provided a novel class of naphthalimide-based lead compounds with exclusive antitumor activities against MCF-7 cell line for further optimization.     

Incrassamarin A–D: Four new 4-substituted coumarins from Calophyllum incrassatum and their biological activities

Four new 4-substituted coumarins, incrassamarin A (1), B (2), C (3) and D (4) with (7S,8S)-7,8-dihydro-5-hydroxy-7,8-dimethyl-4-propyl-2H,6H-benzo[1,2-b;5,4-b’]dipyran-2,6-dione (5), friedelin, carpachromene, amentoflavone, epiafzelechin and L-quercitrin were isolated from the barks and leaves of Calophyllum incrassatum (Guttiferae). The compounds were isolated and purified by size-exclusion recycling HPLC and column chromatographic techniques. The structures of the compounds were determined by spectroscopic means. The compounds were tested for their cytotoxic activity towards MCF-7 and A-549 cell lines and α-glucosidase enzymatic inhibitory activity. Compound (1) displayed cytotoxic activity against A-549 cell lines with IC₅₀ 87.71 μg/mL and showed inhibition towards α-glucosidase enzymatic activity with IC₅₀ 93.25 μM. This is the first report on the isolation of phytochemicals from the barks and leaves of C. incrassatum and their bioactivities.     

Two new rotenoids from the roots of Millettia speciosa

Two new rotenoids, named millettiaosas A–B (1–2), together with four known compounds were isolated from the roots of Millettia speciosa. Their structures were elucidated on the basis of spectroscopic analysis including 1D and 2D NMR techniques and HRESIMS. Evaluation of the two new compounds for cytotoxicity against four human cancer cell lines (MCF-7, HCT-116, A549 and HepG-2) showed moderate activities (10 μM < IC₅₀ < 26 μM).