Antitumor agents. Part 3: synthesis and cytotoxicity of new trans-stilbene benzenesulfonamide derivatives

A new series of trans-stilbene benzenesulfonamide derivatives were designed and synthesized as potential antitumor agents. These new compounds were evaluated in the National Cancer Institute's 60 human tumor cell line in vitro screen. Compounds 9-13 were cytotoxic against several cell lines. Notably, two compounds, 9 and 12, demonstrated selective cytotoxic activity against BT-549 breast cancer (GI(50)=0.205 microM) and HT-29 colon cancer (GI(50)=0.554 microM), respectively.     

Synthesis, structural characterization, and in vitro antitumor activity of novel N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides

A new series of N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamides 23-48 have been synthesized as potential anticancer agents. All compounds were screened for their cytotoxic activity against six human tumor cell lines. The selected compounds 23-27, 30, 31, 33, 35, 38, 42, 45, and 46 were further tested at the US National Cancer Institute for their in vitro activities against a panel of 53-59 human tumor cell lines. The compounds 23-26, 30, 31, 33, 38, 42, 45, and 46 showed 50% growth inhibitory activity in low micromolar concentration (GI(50)=0.03-4.9 microM) against one or more human tumor cell lines (Table 3). The prominent compound with remarkable activity (GI(50)=0.03 microM, TGI=1.3 microM) and selectivity toward melanoma UACC-257 cell line was N-(6-chloro-7-cyano-1,1-dioxo-1,4,2-benzodithiazin-3-yl)-N-(phenyl)-5-bromothiophene-2-sulfonamide 46.     

Synthesis, antiproliferative, and antiplatelet activities of oxime- and methyloxime-containing flavone and isoflavone derivatives

Certain oxime- and methyloxime-containing flavone and isoflavone derivatives were synthesized and evaluated for their antiproliferative activity against three solid cancer cells, human cervical epithelioid carcinoma (HeLa), hepatocellular carcinoma (SKHep1), and oral squamous cell carcinoma (SAS), which are commonly seen in Asian countries, including Taiwan. Selective compounds were also evaluated in the full panel of 60 human tumor cell lines and their mean GI50 values were obtained. The preliminary assays indicated flavone-6-yl derivatives are the most cytotoxic while isoflavone-7-yl derivatives are the best antiplatelet agents. Among them, (E)-6-(2-methoxyiminopropoxy)-2-phenyl-4H-1-benzopyran-4-one (14), (Z)-6-(2-hydroxyimino-2-phenylethoxy)-2-phenyl-4H-1-benzopyran-4-one (18a), and (Z)-6-[2-hydroxyimino-2-(4-methoxyphenyl)ethoxy]-2-phenyl-4H-1-benzopyran-4-one (18c) are three of the best antiproliferative agents with GI50 values of 0.8, 0.7, and 0.8 microM, respectively, against the growth of SKHep1; 0.9, 0.8, and 1.0 microM, respectively, against the growth of HeLa cells. Compound 18c is not only the most cytotoxic with a mean GI50 value of 0.08 microM against the full panel of 60 human tumor cell lines but also the only flavone derivative that exhibited a GI50 value of less than 1 microM against the growth of SAS. Flow cytometric analyses revealed that growth inhibition by 18c was due to accumulation in G2/M phase arrest and followed by apoptosis.     

Antitumor agents 187: synthesis and cytotoxicity of substituted 8,8-dimethyl-2H,8H-pyrano[6,5-h]quinoline-2-one and related compounds

Several substituted 8,8-dimethyl-2H,8H-pyrano[6,5-h]quinoline-2-ones and related compounds were synthesized and evaluated for their in vitro cytotoxicity against a panel of human tumor cell lines. The most active compound (3) showed significant cytotoxic activity with GI50 values in the micromolar range.     

Syntheses and cytotoxicity evaluation of bis(indolyl)thiazole, bis(indolyl)pyrazinone and bis(indolyl)pyrazine: analogues of cytotoxic marine bis(indole) alkaloid

2,4-Bis(3'-indolyl)thiazoles, 3,5-bis(3'-indolyl)-2(1H)pyrazinone and 3,6-bis(3'-indolyl)pyrazine were synthesized and evaluated for cytotoxic activity against diverse human cancer cell lines by the National Cancer Institute. These compounds demonstrated significant inhibitory effects in the growth of a range of cancer cell lines. 2,4-Bis(3'-indolyl)thiazole displayed selective cytotoxicity against certain leukemia cell lines with GI50 values in the low micromolar range while the substituted derivatives showed a broad spectrum of cytotoxic activity. 3,5-Bis(3'-indolyl)-2(1H)pyrazinone and 3,6-bis[3'-(N-methyl-indolyl)]pyrazine possessed strong inhibitory activity against a wide range of human tumor cell lines. The mechanism of action remained unknown. The results suggested that 2,4-bis(3'-indolyl)thiazoles, 3,5-bis(3'-indolyl)-2(1H)pyrazinone and 3,6-bis[3'-(N-methyl-indolyl)] pyrazine offer potential as lead compounds for the discovery of anticancer agents.     

Synthesis and antileukemic activity of 16E-[4-(2-carboxy)ethoxybenzylidene]-androstene amides

In order to determine the structural requirements for cytotoxicity against various tumor cell lines, a new series of 16E-arylidene androstene amides with varying degrees of unsaturation in ring A has been synthesized. Characterization and invitro cytotoxic studies of the newly synthesized compounds are discussed. The compounds on evaluation against various tumor cell lines exhibited significant growth inhibition on leukemia cell lines. 3-Chloro-16E-{[4-(4-methylpiperazin-1-yl)-2-oxoethoxy]benzylidene}androst-5-en-17-one (10) emerged as the most potent compound of the series with GI(50) values of 3.94, 2.61, 6.90 and 1.79μM against CCRF-CEM, K-562, RPMI-8226 and SR leukemia cell lines, respectively.     

Novel imidazole-based combretastatin A-4 analogues: evaluation of their in vitro antitumor activity and molecular modeling study of their binding to the colchicine site of tubulin

The in vitro antitumor activity of novel combretastatin-like 1,5- and 1,2-diaryl-1H-imidazoles was evaluated against the NCI 60 human tumor cell lines panel. Compounds 2d and 2g proved to be more cytotoxic than CA-4 in tests involving their evaluation over a 10(-4)-10(-8) range. Docking experiments showed a good correlation between the MG_MID Log GI(50) values of all these compounds and their calculated interaction energies with the colchicine binding site of alphabeta-tubulin.     

New 2-(1-adamantylcarbonyl)pyridine and 1-acetyladamantane thiosemicarbazones-thiocarbonohydrazones: cell growth inhibitory, antiviral and antimicrobial activity evaluation

The new thiosemicarbazones and thiocarbonohydrazones derived from 2-(1-adamantylcarbonyl)pyridine and 1-acetyladamantane were synthesized and evaluated for their inhibitory effect on tumor cell proliferation and their antiviral and antimicrobial activity. Thiosemicarbazone inhibited tumor cell proliferation (GI50's range: 2.4-100 microM and mean GI50 43.9 microM against various human leukemic cell lines) while thiosemicarbazone and thiocarbonohydrazone 5d exhibited significant inhibition of tumor cell proliferation (GI50's range 2.3-23.6 microM and mean GI50 7.2 microM for and GI50's range 2.4-32.4 microM and mean GI50 12.8microM for ). These GI50 values are comparable to that of 2-acetylpyridine thiosemicarbazone an important lead in TSC's family. The compounds did not afford specific activity against any of the viruses tested when examined at non-toxic concentrations. A weak activity was found for thiocarbonohydrazones against Gram-(+) bacteria (MIC(50) 117.3 and 133 microM, respectively). Using a combination of molecular mechanics calculations and NOE spectroscopy it was shown that the parent compounds and have opposite configuration around C=N bond. Whether this difference in structure can be correlated with the biological activity will be investigated in future studies.     

Synthesis and evaluation of substituted 4-aryloxy- and 4-arylsulfanyl-phenyl-2-aminothiazoles as inhibitors of human breast cancer cell proliferation

Several substituted 4-aryloxy- and 4-arylsulfanyl-phenyl-2-aminothiazoles were synthesized and evaluated for cytotoxic activity against estrogen-positive, estrogen-negative, and adriamycin-resistant human breast cancer cell lines. 4-[4'-(3,4-Dichlorophenoxy)-phenyl]-thiazol-2-yl ammonium iodide demonstrated potent activity against both estrogen-positive and negative breast cancer cell lines with low micromolar (microM) GI(50) values. In addition, we have identified several 2-aminothiazoles that demonstrated selective potency for the adriamycin-resistant and estrogen-negative breast cancer cell lines. The results suggest that these 2-aminothiazoles represent lead compounds for evaluation in animal models of breast cancer.     

Antitumor activity of tetrahydroisoquinoline analogues 3-epi-jorumycin and 3-epi-renieramycin G

Analogues of the tetrahydroisoquinoline family of antitumor antibiotics, 3-epi-jorumycin (3) and 3-epi-renieramycin G (4), in addition to their respective parent natural products (-)-jorumycin (1) and (-)-renieramycin G (2) were evaluated against both human colon (HCT-116) and human lung (A549) cancer cell lines. (-)-Jorumycin (1) displayed potent growth inhibition with GI50 values in the low nanomolar range (1.9-24.3 nM), while compounds 2-4 were found to be substantially less cytotoxic (GI50 0.6-14.0 microM).     

Studies on quinones. Part 42: Synthesis of furylquinone and hydroquinones with antiproliferative activity against human tumor cell lines

The preparation of furyl-1,4-quinone and hydroquinones by reaction of 2-furaldehyde N,N-dimethylhydrazone with benzo- and naphthoquinones is reported. Access to furylnaphthoquinones from unactivated quinones requires acid-induced conditions, however oxidative coupling reactions of activated quinones proceed under neutral conditions. The in vitro cytotoxic activity of the prepared compounds against a panel of three human cancer cell lines has been studied. Most of the furyl-1,4-quinones exhibited good antiproliferative activity (GI(50)=6.5-33.5microm) against the MCF-7, NCI-H460, and SF-268 (CNS cancer) cell lines chosen for testing.     

Synthesis and cytotoxicity evaluation of 6,11-dihydro-pyridazo- and 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-diones

The 6,11-dihydro-pyridazo[2,3-b]phenazine-6,11-dione and 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-dione derivatives were synthesized from 6,7-dichloro-5,8-phthalazinedione and 6,7-dichloro-5,8-quinolinedione, respectively, producing a series of new anticancer drugs. The cytotoxic activities of the prepared compounds were evaluated by a SRB (Sulforhodamine B) assay against the following tumor cell lines: A459 (human lung), SK-OV-3 (human ovarian), SK-MEL-2 (human melanoma), XF498 (human CNS), and HCT 15 (human colon). Almost all the derivatives of the 6,11-dihydro-pyridazo[2[,3-b]phenazine-6,11-dione and 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-dione, tetracyclic heteroquinone analogues with four or three nitrogen atoms, exhibited excellent cytotoxicity on almost all the human tumor cell lines tested. Specifically, 6,11-dihydro-pyridazo[2,3-b]phenazine-6,11-dione (4a) exhibited potent activity against all the tumor cell lines, and in particular, its cytotoxic effect against HCT 15 (ED(50)=0.004 microg/mL) was 25 times greater than that of doxorubicin (ED(50)=0.093 microg/mL).     

3,5-bis(3'-indolyl)pyrazoles, analogues of marine alkaloid nortopsentin: synthesis and antitumor properties

A series of 10 bis-indolylpyrazoles of type 9, 10 were obtained by cyclization of diketones 8 using hydrazine monohydrate or methylhydrazine in refluxing acetic acid/THF. Derivatives 9a,c,d were selected, by the National Cancer Institute (NCI, Bethesda, USA), to be evaluated against the full panel of about 60 human tumor cell lines derived from nine human cancer cell types and showed antiproliferative activity in the micromolar range. In particular, 9d, the most active compound was effective against all the tested cell lines with a GI(50) mean value of 3.23 microM; TGI and LC(50) values were 14.5 and 58.9 microM having positive response on 91% and 41% of the tested cell lines, respectively.     

Novel 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues as cytotoxic agents

A series of 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues were synthesized and evaluated for cytotoxic activity against eight human cancer cell lines. Compounds 18, 21, 28, 29, 30 and 31 showed cytotoxic activity with GI(50) values in the range of 2.1-8.1 microM concentration. Among these, compounds 21 and 28 exhibited good pharmacokinetic properties. These compounds were further evaluated for their in vivo efficacy in modified hollow fibre assay (HFA).     

Design and synthesis of diarylamines and diarylethers as cytotoxic antitumor agents

Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino-3-nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI(50) values ranging from 0.33 to 3.45μM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta-chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC(50) values of 2.2-3.0μM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase.     

Design, synthesis, and in vitro antitumor activity of new 1,4-diarylimidazole-2-ones and their 2-thione analogues

A series of new 1,4-diarylimidazol-2(3H)-one derivatives and their 2-thione analogues has been prepared and evaluated in vitro for antitumor activity against the NCI human cancer cell panel. Compounds bearing a 3,4,5-trimethoxyphenyl ring linked to either N-1 or C-4 position of the imidazole core demonstrated an interesting profile of cytotoxicity with preferential activity against leukemic cell lines. Compound 13 exhibited a potent antitumor activity against MOLT-4 (GI(50)=20 nM) and SR (GI(50)=32 nM) cell lines.     

Synthesis and cytotoxic activities of 1-benzylidine substituted beta-carboline derivatives

A series of new beta-carboline derivatives, bearing a benzylidine substituent at position-1, has been prepared and evaluated in vitro against a panel of human cell lines. The N(2)-benzylated beta-carbolinium bromates represented the most interesting cytotoxic activities. In particular, compounds 19 were found to be the most potent compounds with IC(50) values lower than 5 microM against 10 strains human tumor cell lines. These results confirmed that the N(2)-benzyl substituent on the beta-carboline ring played an important role in the modulation of the cytotoxic activities and suggested that further development of such compounds may be interest.     

Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents

We designed, synthesized and evaluated 13 novel tricyclic indeno[2,1-d]pyrimidines as RTK inhibitors. These analogues were synthesized via a Dieckmann condensation of 1,2-phenylenediacetonitrile followed by cyclocondensation with guanidine carbonate to afford the 2-amino-3,9-dihydro-indeno[2,1-d]pyrimidin-4-one. Sulfonation of the 4-position followed by displacement with appropriately substituted anilines afforded the target compounds. These compounds were potent inhibitors of platelet-derived growth factor receptor β (PDGFRβ) and inhibited angiogenesis in the chicken embryo chorioallantonic membrane (CAM) assay compared to standards. In addition, compound 7 had a two digit nanomolar GI(50) against nine tumor cell lines, a submicromolar GI(50) against 29 of other tumor cell lines in the preclinical NCI 60 tumor cell line panel. Compound 7 also demonstrated significant in vivo inhibition of tumor growth and angiogenesis in a B16-F10 syngeneic mouse melanoma model.     

Novel antiproliferative analogs of the Taq DNA polymerase inhibitor catalpol

The naturally occurring iridoid catalpol (1) is a Taq DNA polymerase inhibitor. However, its poor lipophilicity might account for the lack of biological activity against human solid tumor cell lines. The traditional prodrug approach by means of peracetylation of the free hydroxyl groups led to a compound, which showed a marginal growth inhibition against the most sensitive cell line A2780 (ovarian cancer). However, the formation of analogs bearing one to three silyl ether groups led to antiproliferative compounds against a panel of six human solid tumor cell lines, with GI50 values in the range 1.8-4.8 microM. Cell cycle studies revealed arrest in G0/G1 phase that is consistent with DNA polymerase inhibition.     

Artelastin is a cytotoxic prenylated flavone that disturbs microtubules and interferes with DNA replication in MCF-7 human breast cancer cells

Artelastin, a novel prenylated flavone, previously isolated from the wood bark of Artocarpus elasticus, was evaluated for its capacity to inhibit the growth of fifty-two human tumor cell lines, representing nine different tumor types. A pronounced dose-dependent growth inhibitory effect was detected in all the cell lines, with GI50 values ranging from 0.8-20.8 microM. Studies to elucidate the basis of the growth inhibitory activity of artelastin were performed in the MCF-7 human breast cancer cell line (GI50 = 6.0 microM). We show that artelastin exerts a biphasic effect in the DNA synthesis of MCF-7 cells, a stimulatory effect at low concentrations (below GI50) for short times of exposition (6 h and 24 h), and an inhibitory effect at high concentrations (above GI50). Remarkably, treated cells that have DNA synthesis affected could be viable and metabolically active. Furthermore, artelastin acts as a cytotoxic rather than a cytostatic compound. Massive cytoplasmatic vacuoles were detected in cells after artelastin treatment. Together with these morphological alterations, cells show the presence of abnormal nuclear morphologies, and occasionally nuclear condensation, which were identified as apoptotic by TUNEL assay. Moreover, artelastin was shown to disturb the microtubule network while no effect was observed on the kinetochores. Flow cytometry analysis of cells treated with artelastin reveal an accumulation in S phase that interferes with the cell cycle progression. Additionally, according to BrdU patterns, studies with synchronized cells at G0 and at G1/S transition also suggest that artelastin delays DNA replication since progression of cells trough S-phase is perturbed.