Synthesis, X-ray crystallographic analysis, and antitumor activity of 1-acyl-3,6-disubstituted phenyl-1,4-dihydro-1,2,4,5-tetrazines

Eleven compounds of 1-acyl-3,6-disubstituted phenyl-1,4-dihydro-1,2,4,5-tetrazines were prepared from 3,6-disubstituted phenyl-1,2-dihydro-1,2,4,5-tetrazines and anhydrides or acyl chlorines, and their structures were confirmed by single-crystal X-ray diffraction and the semi-empirical calculation of PM3 method. This reaction yields the 1,4-dihydro derivatives rather than the 1,2-dihydro derivatives. The central six-membered ring of these compounds has an obvious boat conformation and therefore is not homoaromatic. Their antitumor activities were evaluated in vitro by the SRB method for A-549 cell and the MTT method for P-388 cells. The results show that there is one compound which is highly effective against A-549 cells and two compounds which are highly effective against P-388 cells. Thus, this compound possesses potential antitumor activities and is worth researching further.     

Synthesis, structure analysis, and antitumor activity of 3,6-disubstituted-1,4-dihydro-1,2,4,5-tetrazine derivatives

Fourteen compounds of 3,6-disubstituted-1,4-dihydro-1,2,4,5-tetrazine derivatives were prepared and their structures were confirmed by single-crystal X-ray diffraction and the semi-empirical calculation of PM3 method. This reaction yields the 1,4-dihydro derivatives rather than the 1,2-dihydro derivatives. The central six-membered ring of 1,4-dihydro-1,2,4,5-tetrazine has a chair conformation and therefore is not homoaromatic. Their antitumor activities were evaluated in vitro by SRB method for A-549 and BEL-7402 cells, and MTT method for P-388 and HL-60 cells. The results show that there is one compound which is highly effective against P-388 cells and one compound which is highly effective against HL-60 cells. So it is a kind of compound which possesses potential antitumor activities and is worth to research further.     

Synthesis and biological evaluation of new spin-labeled derivatives of podophyllotoxin

In order to find compounds with superior bioactivity and less toxicity, a series of spin-labeled podophyllotoxin derivatives were synthesized and tested for the partition coefficients and cytotoxicity against P-388 and A-549. Furthermore, we also determined antioxidant activities of target molecular in tissues of SD rats by the TBA method. Results revealed that most synthesized compounds showed more significant cytotoxicity against P-388 and A-549 in vitro than VP-16. Among them, 9d exhibited most potent cytotoxicity against P-388 and A-549 cells (IC50 is <0.01 and 0.13 microM, respectively). Also, the antioxidative activities showed that the modified compounds of 4'-demethylepipodophyllotoxin (9a-d and 10a-c) are higher than those of podophyllotoxin series (8a-d). The relationship between the cytotoxicity and antioxidative activity discussed.     

Synthesis and anticancer activity of thiosemicarbazones

Twenty-six thiosemicarbazones (III-1-III-26) were synthesized via three steps starting from hydrazine hydrate and carbon disulfide. The testing of anticancer activity of these compounds in vitro against P-388, A-549, and SGC-7901 shows that compounds III-15 and III-16 possess a higher inhibitory ability for P-388 and SGC-7901. Further testing shows that the value of IC50 of compound III-16 against SGC-7901 reaches to 0.032 microM.     

Synthesis and antitumor activity of 10-substituted benzylidene anthrone

Fifteen compounds of 10-substituted benzylidene anthrone were prepared with moderate yield by reaction of anthrone and substituted benzaldehydes under the presence of pyridine and piperidine as catalyst. Their antitumor activities in vitro were evaluated. The results show that the electron-withdrawing substitutes decrease the activities, the electron-donor substitutes increase the activities; the compound with substitute at ortho or para position has stronger activities than that of compound with the same substitute but located at the meta position. There are six compounds which appear as strong effective inhibition for A-549 cancer cell growth. This is a kind of good leading compound which is worth researching further.     

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.     

Synthesis and antitumor evaluation of a novel series of triaminotriazine derivatives

A series of triaminotriazine derivatives (compounds 5a-f, 6a-x, and 7a-g) was designed, synthesized, and evaluated for their inhibition activities to colorectal cancer (CRC) cell lines (HCT-116 and HT-29). Most of the synthesized compounds demonstrated moderate anti-proliferatory effects on both HCT-116 and HT-29 cell lines at the concentration of 10 microM. The inhibitory activities against HCT-116 and HT-29 cell lines were discussed to develop the structure-activity relationships of this new series. Compounds 6l and 6o exhibited prominent inhibition activities toward HCT-116, with IC50s of 0.76 and 0.92 microM, respectively. The in vivo antitumor studies and pharmacokinetics of compound 6l showed that it might be a promising new hit for further development of antitumor agents.     

Synthesis and anticancer evaluation of bis(benzimidazoles), bis(benzoxazoles), and benzothiazoles

Four classes of UK-1 analogues were synthesized and their cytotoxicity testing against human A-549, BFTC-905, RD, MES-SA, and HeLa carcinoma cell lines was determined. The results revealed that UK-1 and four of these analogues (15-18) are potent against the cancer cell lines. In particular, compound 16 is more potent than UK-1 against A-549 and HeLa cell lines, and compounds 15, 17, and 18 selectively exhibit potent cytotoxic activity against the BFTV-905 cells (IC50 9.6 microM), A-549 cells (IC50 6.6 microM), and MES-SA cells (IC50 9.2 microM), respectively.     

Synthesis and biological evaluation of 7-alkenyl homocamptothecins as potent topoisomerase I inhibitors

Homocamptothecin (hCPT) is a camptothecin (CPT) derivative with a seven-membered β-hydroxylactone E ring, which shows higher lactone stability and improves topoisomerase I (Topo I) inhibition activity. In an attempt to improve the antitumor activity of homocamptothecins, a series of 7-alkenyl-homocamptothecin derivatives was designed and synthesized based on a semisynthetic route starting from CPT. Most of the synthesized compounds exhibit higher cytotoxic activities on the A-549 tumor cell line than topotecan (TPT). Some compounds such as 2a and 2o show a broad in vitro antitumor spectrum and exhibit superior Topo I-inhibition activity.     

Polyketides from Penicillium sp. JP-1, an endophytic fungus associated with the mangrove plant Aegiceras corniculatum

Four polyketides, leptosphaerone C (1), penicillenone (2), arugosin I (3) and 9-demethyl FR-901235 (4), as well as five known compounds, bacillosporin A (5), bacillosporin C (6), sequoiamonascin D (7), sequoiatone A (8), and sequoiatone B (9) were isolated from the Penicillium sp. JP-1, an endophytic fungus isolated from Aegiceras corniculatum. Their structures were determined by spectroscopic methods, mainly by 2D NMR spectroscopic analyses. Compound 1 showed cytotoxicity against A-549 cells with an IC50 value of 1.45 microM, while compound 2 showed cytotoxicity against P388 cells with an IC50 value of 1.38 microM.     

3Beta-hydroxy-6-aza-cholestane and related analogues as phosphatidylinositol specific phospholipase C (PI-PLC) inhibitors with antitumor activity

6-Aza steroid analogues were synthesized as PI-PLC inhibitors. The most active compound, 3beta-hydroxy-6-aza-cholestane (1) showed potent PI-PLC inhibition (IC50 = 1.8 microM), similar to that of the commercially available steroid analogue U73122 (IC50 = 1-2.1 microM). Compound 1 exhibited significant growth inhibition effects (IC50 = 1.3 microM in each case) against MCF-7 and HT-29 cancer cells in in vitro cell culture. Compound 1 also inhibited the in vitro adhesion and transmigration of HT-1080 fibrosarcoma cells at 2.5 and 5.0 microM, respectively. In vivo, compound 1, at 1 mg/kg/day, reduced the volume of MCF-7 tumors in xenograft models, without weight loss in mice. Structure activity relationships of this series of compounds revealed that a hydrophobic cholesteryl side chain, 3beta-hydroxy group and a C-6 nitrogen containing a hydrogen atom at position-6 are crucial for activity. N-Maleic amidoacid derivative 11 also exhibited weak inhibition (IC50 = 16.2 microM).     

Novel synthetic isoquinolino[5,4-ab]phenazines: inhibition toward topoisomerase I, antitumor and DNA photo-cleaving activities

The novel DNA interactive isoquinolino[5,4-ab]phenazine derivatives were designed and synthesized. Their inhibitory abilities toward topoisomerase I, antitumor activities and DNA photo-cleaving abilities were examined. The substituents at peri sites of two phenazine N atoms played very important roles for all these biological activities. At a concentration of 100 microM, all these phenazine derivatives (but A2 and A6) exhibited an inhibitory activity toward topoisomerase I. A6 had efficient antitumor activities against both human lung cancer cell (A549) and murine leukemia cell (P388). A1, A5, and A6 exhibited antitumor activities selectively against P388. A2 was the most efficient DNA photocleaver, which had converted supercoiled DNA from form I to form II at <1 microM. Under anaerobic conditions, the electron transfer mechanism mainly contributed to DNA photo-induced cleavage, while under aerobic conditions, superoxide anion was also involved in this process.     

Novel promising 4-anilinoquinazoline-based derivatives as multi-target RTKs inhibitors: Design,molecular docking,synthesis, and antitumor activities in vitro and vivo

4-Anilinoquinazoline derivatives function as tyrosine kinase inhibitors (TKIs). Novel TKIs are needed for cancer mutations and drug-resistant cells. We designed and synthesized 4-anilinoquinazoline derivatives with substitutions at quinazoline positions 6, 7 and 4 using a binding model with multi-target receptor tyrosine kinases, and assessed their antitumor activity against five human tumor cell lines (HepG2, A549, MCF-7, DU145, SH-SY5Y). The majority of the compounds inhibited the proliferation of all the cancer cell types, with some compounds displaying selective inhibition. Compounds 21, 25, 27, and 37 displayed IC₅₀ values of 7.588, 8.619, 6.936, and 8.516 μM, respectively, for A549 cells, which were much lower than that of Gefitinib (14.803 μM). Compound 32 displayed an IC₅₀ value of 2.756 μM for DU145 cells. The representative compound 40 had unexceptionable broad-spectrum inhibition for all cancer cell types, and demonstrate inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-β), and epidermal growth factor receptor (EGFR) with IC₅₀ values of 46.4, 673.6 and 384.8 nM, respectively, which were similar to those of Sorafenib for VEGFR-2 and PDGFR-β (140.6 and 582.7 nM, respectively). Molecular docking results supported the molecular level assay results. Data for production of reactive oxygen species and assessment of matrix metalloproteinase corroborated the strong anti-proliferative effect of compound 40. The compound also displayed robust antitumor efficacy and relativity lower toxicity in a xenograft model. These attributes were similar to those of Sorafenib. Compound 40 drug warrants further study as a candidate.     

Effects of 9,10-dihydroxy-4,4-dimethyl-5,8-dihydro-1(4H)-anthracenone derivatives on tumor cell respiration

A series of tricyclic hydroquinones, incorporating a carbonyl group in the ortho position relative to the phenol function, were tested as inhibitors of oxygen uptake against the TA3 mouse carcinoma cell line and its multidrug-resistant variant TA3-MTX-R. The title compound, which proved to be the most active one, also exhibited low micromolar dose-dependent growth inhibition of the human tumor U937 cell line (human monocytic leukemia). A tentative structure-activity relationship is proposed for these substances. A comparison between the cytotoxicities of the title compound and 4,4-dimethyl-5,8-dihydroxynaphthalene-1-one, with their activities as inhibitors of oxygen uptake by the TA3-MTX-R cell line, is presented. Also, the inhibition of oxygen uptake by 6-(4-methylpent-3-enyl)-1,4-naphthoquinone was determined and compared with its reported cytotoxicity toward P-388 (murine lymphocytic leukemia), A-549 (human lung carcinoma), HT-29 (human colon carcinoma), and MEL-28 (human melanoma) cells. The inhibition of oxygen uptake by TA3-MTX-R cells is useful as a quick test for preliminary screening of possible anticancer activity.     

Synthesis, characterization and in vitro anti-tumor activities of matrine derivatives

Nineteen previously unreported matrine derivatives were synthesized and characterized using elemental analysis, infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and mass spectrometry. Target compounds 6a-6l and 7a-7c showed stronger inhibitory activities than matrine in the in vitro antitumor tests and inhibited the growth of the Hep7402, B16-F10, A549, and TW03 cell lines. In addition, compound 6i exhibited a potent antitumor activity similar to that of colchicine.     

Pharmaco-toxicological study of Kageneckia oblonga, Rosaceae

The probable antipyretic, antiinflammatory, analgesic and antioxidant properties of Kageneckia oblonga, Rosaceae, were investigated and the major compounds of its active extracts were isolated. The study comprised the acute toxicity of the extracts of global methanol, hexane, dichloromethane and methanol. The cytotoxicity of global methanol extract was studied in three tumoral cell lines. All the extracts exhibited the pharmacological activities under study. Methanol and dichloromethane were the most toxic extracts. From the global methanol extract, isolations were performed of prunasin, 23,24- dihydro-cucurbitacin F, and a new cucurbitacin, 3beta-(beta-D-glucosyloxy)-16alpha,23alpha-epoxycucurbita-5,24-diene-11-one. The cytotoxicity of both cucurbitacins on human neutrophils at the assayed concentrations was not statistically significant. In-vitro assays showed that both cucurbitacins can be partly responsible for the analgesic, antipyretic, and anti-inflammatory activities. Evaluation was done of the cytotoxicity of global methanol extract, 23, 24-dihydrocucurbitacin F, aqueous extracts and prunasin against P-388 murine leukaemia, A-549 human lung carcinoma and HT-29 colon carcinoma. Since global methanol extract presented a strong cytotoxicity against P-388 murine leukaemia, A-549 human lung carcinoma, and HT-29 cell lines, it is highly probable that this extract contain one or more cytotoxic compounds that could be investigated for their potential use as an agent against cancer.     

Novel heterocyclic family of phenyl naphthothiazole carboxamides derived from naphthalimides: synthesis, antitumor evaluation, and DNA photocleavage

A new heterocyclic family of (2-(dimethylamino)ethyl)-2-substituted phenylnaphtho[2,1-d]thiazole-5-carboxamides modified from naphthalimides was designed, synthesized, and quantitatively evaluated as antitumor agents and photonucleases. All these compounds were found to be more cytotoxic against P388 than against A549. B(3) (m-NO(2)) was found to be the strongest inhibitor for P388 with IC(50) of 1.49 microM, while B(2) was the most cytotoxic compound against A549 with IC(50) of 12 microM. B(4) (p-CH(3)), the most efficient DNA photocleaver, showed detectable DNA cleavage at 0.5 microM and total cleavage from form I to 100% form II at 50 microM. The photocleaving mechanism was changed with the modification to be via superoxide anion and radical.     

Synthesis of 4β-carbamoyl epipodophyllotoxins as potential antitumour agents

A series of new 4β-carbamoyl epipodophyllotoxin analogues have been synthesized and evaluated for their anticancer activity against eleven cancer cell lines including Zr-75-1, MCF7, KB, Gurav, DWD, Colo 205, A-549, Hop62, PC3, SiHa and A-2780. Most of the compounds exhibited better growth-inhibition activities against tested cell lines than that of etoposide. Further, compounds 6g and 6i are also evaluated for their DNA topoisomerase-II (topo-II) inhibition activity and they exhibited significant inhibition of topo-II catalytic activity comparable to etoposide.     

Synthesis, antitumor and anti-HIV activities of benzodithiazine-dioxides

Several 8-chloro-7-R1-6-R2-3-R3-imidazo[1,2-b][1,4,2]benzodithiazine 5,5-dioxide derivatives (9-11, 16-19, and 21-24) have been synthesized as potential antitumor or anti-HIV agents. The in vitro antitumor and anti-HIV-1 activities of the compounds were determined in a panel of cell lines. The benzodithiazine-dioxide 10 showed 50% growth inhibitory activity in low micromolar against most cells. It was particularly effective in leukemia, lung, melanoma, ovarian, and renal cancer cells with GI50 values of 1-2 microM. Interestingly, benzodithiazine-dioxide 16 showed remarkable anti-HIV-1 activity with 50% effective concentration EC50 value of 0.94 microM and no significant cytotoxicity at 200.0 microM.     

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.