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Recently, proteolysis targeting chimera (PROTAC) technology is highlighted in drug discovery area as a new therapeutic approach. PROTAC as a heterobifunctional molecule is comprised of two ligands, which recruit target protein and E3 ligase, respectively. To degrade the anaplastic lymphoma kinase (ALK) fusion protein, such as NPM-ALK or EML4-ALK, we generated several ALK-PROTAC molecules consisted of ceritinib, one of the ALK inhibitors, and ligand of von Hippel-Lindau (VHL) E3 ligase. Among these molecules, TD-004 effectively induced ALK degradation and inhibited the growth of ALK fusion positive cell lines, SU-DHL-1 and H3122. We also confirmed that TD-004 significantly reduced the tumor growth in H3122 xenograft model.

Bromodomain-containing protein 4 (Brd4) is known to play a key role in tumorigenesis. It binds acetylated histones to regulate the expression of numerous genes. Because of the importance of brd4 in tumorigenesis, much research has been undertaken to develop brd4 inhibitors with therapeutic potential. As a result, various scaffolds for bromodomain inhibitors have been identified. To discover new scaffolds, we performed mid-throughput screening using two different enzyme assays, alpha-screen and ELISA. We found a novel bromodomain inhibitor with a unique scaffold, aristoyagonine. This natural compound showed inhibitory activity in vitro and tumor growth inhibition in a Ty82-xenograft mouse model. In addition, we tested Brd4 inhibitors in gastric cancer cell lines, and found that aristoyagonine exerted cytotoxicity not only in I-BET-762-sensitive cancer cells, but also in I-BET-762-resistant cancer cells. This is the first paper to describe a natural compound as a Brd4 bromodomain inhibitor.

Gastric cancer is a malignancy that has a high mortality rate. Although progress has been made in the treatment of gastric cancer, many patients experience cancer recurrence and metastasis. Folate receptor 1 (FOLR1) is overexpressed on the cell surface in over one-third of gastric cancer patients, but rarely is expressed in normal tissue. This makes FOLR1 a potential target for chimeric antigen receptor (CAR) T cell immunotherapy, although the function of FOLR1 has not been elucidated. CAR are engineered fusion receptor composed of an antigen recognition region and signaling domains. T cells expressing CAR have specific activation and cytotoxic effects against cancer cells containing the target antigen. In this study, we generated a CAR that targets FOLR1 composed of a single-chain variable fragment (scFv) of FOLR1 antibody and signaling domains consisting of CD28 and CD3ζ. Both FOLR1-CAR KHYG-1, a natural killer cell line, and FOLR1-CAR T cells recognized FOLR1-positive gastric cancer cells in a MHC-independent manner and induced secretion of various cytokines and caused cell death. Conclusively, this is the first study to demonstrate that CAR KHYG-1/T cells targeting FOLR1 are effective against FOLR1-positive gastric cancer cells.

Drug delivery using thermosensitive liposomes (TSL) has significant potential for tumor drug targeting and can be combined with local hyperthermia to trigger drug release. Although TSL-mediated drug delivery can be effective by itself, we developed doxorubicin (DOX)-containing CO2 bubble-generating TSL (TSL-C) that were found to enhance the antitumor effects of DOX owing to the synergism between burst release of drug and hyperthermia-induced CO2 generation. An ultrasound imaging system was used to monitor hyperthermia-induced CO2 generation in TSL-C and the results revealed that hyperthermia-induced CO2 generation in TSL-C led to increased DOX release compared to that observed for non-CO2-generating TSL. Moreover, TSL-C significantly inhibited the tumor growth in MDA-MB-231 tumor-bearing mice compared to TSL (p

Here, we show the newly synthesized and potent ALK inhibitor having similar scaffold to KRCA-0008, which was reported previously, and its molecular mechanism against cancer cells harboring EML4-ALK fusion protein. Through ALK wild type enzyme assay, we selected two compounds, KRCA-0080 and KRCA-0087, which have trifluoromethyl instead of chloride in R2 position. We characterized these newly synthesized compounds by in vitro and in vivo assays. Enzyme assay shows that KRCA-0080 is more potent against various ALK mutants, including L1196M, G1202R, T1151_L1152insT, and C1156Y, which are seen in crizotinib-resistant patients, than KRCA-0008 is. Cell based assays demonstrate our compounds downregulate the cellular signaling, such as Akt and Erk, by suppressing ALK activity to inhibit the proliferation of the cells harboring EML4-ALK. Interestingly, our compounds induced strong G1/S arrest in H3122 cells leading to the apoptosis, which is proved by PARP-1 cleavage. In vivo H3122 xenograft assay, we found that KRCA-0080 shows significant reduction in tumor size compared to crizotinib and KRCA-0008 by 15–20%. Conclusively, we report a potent ALK inhibitor which shows significant in vivo efficacy as well as excellent inhibitory activity against various ALK mutants.

Bromodomain-containing protein 4 (BRD4) is known to regulate the expression of c-Myc to control the proliferation of cancer cells. Therefore, development of small-molecule inhibitors targeting the bromodomain has been widely studied. However, some clinical trials on BRD4 inhibitors have shown its drawbacks such as toxicity including the loss of organ weight. Here, we report the development of the novel and promising scaffold, 1H-indazol-4,7-dione, as a bromodomain inhibitor and synthesized derivatives for the inhibition of binding of bromodomain to acetylated histone peptide. Through this effort, we obtained 6-chloro-5-((2,6-difluorophenyl)amino)-1H-indazole-4,7-dione (5i), which showed a highly potent activity with a half-maximal inhibitory concentration (IC50) of 60 nM. The in vivo xenograft assay confirmed that the 1H-indazol-4,7-dione compound reduced the tumor size significantly. These results show that the 1H-indazol-4,7-dione scaffold is highly potent against bromodomain.

In this study, a series of novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety was described for ALK inhibitor. The pyrazole, imidazole, 1,2,4-triazole, piperazine and phenanthridine moieties were employed at the 2-position of pyrimidine. Among the compounds synthesized, 28, 29, 36, and 42 showed promising anti-ALK activities in enzymatic- and cell-based assays. In vivo H3122 xenograft model study showed that compound 29 effectively suppressed ALK-driven tumor growth, similar to the extent of ceritinib, suggesting that it could be used for a novel ALK inhibitor development.

A series of triazolopyridazines substituted with methylisoquinolinone were designed and synthesized. Some of the triazolopyridazines strongly inhibited c-Met kinase and showed good anti-proliferative activity against a panel of c-Met-amplified gastric cancer cell lines (MKN-45, SNU-5 and Hs746T).

We report the synthesis and biological evaluation of aminopyridines substituted with benzoxazole. The SAR of the aminopyridines was explored to improve the inhibitory activity against c-Met and to decrease hERG affinity. These studies led to the discovery of amide 24 which showed good c-Met inhibitory potency, low affinity to hERG and favorable pharmacokinetic properties in rats.

Studies on antitumor heterocyclic quinones containing nitrogens revealed that the number and position of nitrogens on the heterocyclic ring have significance on cytotoxicity of quinones. In our continuous effort to find more cytotoxic quinone compounds, we designed triazolophthalazine analogues in order to introduce more nitrogens on the heterocyclic quinones. 1-/2-Substituted-[1,2,3]triazolo[4,5-g]phthalazine-4,9-diones were synthesized by 1,3-dipolar addition of phthalazine-5,8-dione and 4-methoxybenzyl azide by modification of previously reported method. The cytotoxicity of the synthesized compounds was evaluated by a SRB (sulforhodamine B) assay against nine types of human cancer cell lines and inhibition against topoisomerase II (Topo II) of them was assessed by a decatenation assay. Most of the synthesized compounds showed considerably higher cytotoxicity than that of doxorubicin. Also, topoisomerase II inhibitory activity of the tested compounds was higher than that of etoposide and IC(50) values of the compounds were 19.4-64.5 microM.

Ceritinib, an ALK inhibitor, was hurriedly approved by the US FDA last year, and demonstrates impressive results in EML4-ALK positive patients. To get a superior ALK inhibitor, we synthesized several ceritinib derivatives with minor modifications to the phenylpiperidine moiety. Biochemical and cellular assays demonstrated the improved activity of KRCA-386 over that of ceritinib. KRCA-386 has superior inhibitory activity against ALK mutants commonly found in crizotinib-resistant patients. Particularly, KRCA-386 has considerably greater activity than ceritinib against the G1202R mutant, one of the most challenging mutations to overcome. The cell cycle analysis indicates that ALK inhibitors induce G1/S arrest, resulting in apoptosis. The in vivo xenograft data also demonstrate that KRCA-386 is significantly better than ceritinib. KRCA-386 dosed at 25 mpk caused 105% tumor growth inhibition (TGI) compared to 72% TGI with ceritinib dosed at 25 mpk. ( n = 8, P = 0.010) The kinase profiling assay revealed that several kinases, which are known to be critical for tumor growth, are inhibited by KRCA-386, but not by ceritinib. We anticipate that this characteristic of KRCA-386 enhances its in vivo efficacy. In addition, KRCA-386 shows excellent blood brain barrier penetration compared to ceritinib. These results suggest that KRCA-386 could be useful for crizotinib-resistant patients with brain metastases.

A series of novel 2,4-diaminopyrimidines bearing tetrahydronaphthalenyl moiety were synthesized and evaluated for their anti-anaplastic lymphoma kinase (ALK) activities using enzymatic and cell-based assays. Among the compounds synthesized, compound 17b showed promising pharmacological results in in vitro, ex vivo, and pharmacokinetic studies. An in vivo efficacy study with compound 17b demonstrated highly potent inhibitory activity in H3122 tumor xenograft model mice. A series of kinase assays showed that compound 17b inhibited various kinases including FAK, ACK1, FGFR, RSK1, IGF-1R, among others, thus demonstrating its potential for synergistic anti-tumor activity and development as a multi-targeted non-small cell lung cancer (NSCLC) therapy.

Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378.

A series of novel 2,4-diaminopyrimidine compounds bearing bicyclic aminobenzazepine were synthesized and evaluated for their anti-ALK activities. The activities of these compounds were confirmed in both enzyme- and cell-based ALK assays. Amongst compounds synthesized, KRCA-0445 showed very promising results in pharmacokinetic study and in vivo efficacy study with H3122 xenograft mouse model.

A series of 1-substituted 2-methyl-1H-imidazo[4,5-g]phthalazine-4,9-dione derivatives 8 was synthesized from 6,7-dichlorophthalazine-5,8-dione 5 and evaluated for in vitro cytotoxicity against several human tumor cell lines. Most of the tested compounds showed potential cytotoxic activity considerably higher than that of the reference compounds, ellipticine and doxorubicin.

A new series of hematoporphyrin-platinum(II) conjugates was prepared by platination of the glutamate ligand tethered to hydrophilic hematoporphyrin derivatives, in which different numbers of ethylene oxide unit were introduced to modulate the hydrophobic/hydrophilic balance of the conjugates. The antitumor activity of the hematoporphyrin-platinum(II) conjugates was assayed in vitro and in vivo against the leukemia L1210 cell line. Among the complexes, compound 11 exhibited not only higher in vivo activity (T/C% = 192) than cisplatin (T/C% = 184) and carboplatin (T/C% = 168), but also elevated tumor-localizing effect (tumor/muscle ratio > 3).

For the development of new anticancer agents, phenyl, 2-pyridyl, 2-furyl, 2-thienyl, 2-furylvinyl and 2-thienylvinyl substituted derivatives on 2,4,6-position in pyridine moiety were prepared and evaluated for their topoisomerase I inhibitory activity. Among the thirteen prepared compounds, four compounds exhibited strong topoisomerase I inhibitory activity. A structure-activity relationship study indicated that the 2-thienyl-4-furylpyridine skeleton was important for topoisomerase I inhibitory activity.

In order to further determine the nature of structure-activity relationship on the cytotoxicities of saponins with 1-->2 and 1-->3 linkages of disaccharides, we isolated guaianin N, collinsonidin, kalopanaxsaponin A and hederoside D(2) as disaccharides, and patrinia glycoside B-II as a trisaccharide, from the n-BuOH extract of Akebia quinata (Lardizabalaceae). Complete acid hydrolysis of the extract afforded oleanolic acid (1) and hederagenin (2). By sulforhodamine B (SRB) assay, kalopanaxsaponin A containing an alpha-L-rhap-(1-->2)-alpha-L-arap moiety exhibited distinctly higher cytotoxicity (IC(50) 1.8-2.7 microg/ml) against all of the tested cell lines than the other saponins (IC(50), 4-8 microg/ml). These results suggest that the alpha-L-rhap-(1-->2)-alpha-L-arap moiety has a unique structural significance in terms of its cell biochemistry, compared to those oleanane glycosides with other sugar linkages. On the other hand, kalopanaxsaponin A exhibited a significant inhibitory effect on nitric oxide production by lipopolysaccharide (LPS)-activated macrophage 264.7, whereas other saponins had weaker activities.

Reaction between 2,3-dichloronaphthoquinone ( I ) and ethyl cyanoacetate or diethyl malonate under different conditions gave the starting materials, 2-chloro-3-(α-cyano-α-ethoxycarbonyl-methyl)-1,4-naphthoquinone ( A ) or 2-chloro-3-(diethoxycarbonyl-methyl)-1,4-naphthoquinone ( B ). The 2-amino-3-ethoxycarbonyl -N- substituted-benzo[ f ]indole-4,9-dione derivatives [ A-(1 – 10) ] and 2-hydroxy-3-ethoxycarbonyl -N- substituted-benzo[ f ]indole-4,9-dione derivatives [ B-(1 – 12) ] were prepared from compounds A and B , respectively, by using various alkyl-, and arylamines. The cytotoxic activities of the prepared compounds were evaluated by 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). Many of the derivatives mentioned exhibited more potent cytotoxic effects against SK-OV-3 and XF498 than etoposide. Significantly, 2-amino-3-ethoxycarbonyl -N- (3-methyl-phenyl)-benzo[ f ]indole-4,9-dione ( A-8 ) showed potent activity against all tumor cell lines, and in particular, its cytotoxic effect against SK-OV-3 was much higher than doxorubicin.

6,11-Dihydro-pyrido[2,3-b]phenazine-6,11-diones and 6,11-dihydro-benzo[2,3-b]phenazine-6,11-diones were synthesized from 6,7-dichloro-5,8-quinolinedione and 2,3-dichloro-1,4-naphthoquinone. The study on the cytotoxicity on these products revealed that the pyridophenazinediones, tetracyclic heteroquinone analogues with three nitrogen atoms exhibited a high cytotoxicity on several human tumor cell lines. Compound 9c and 9e showed in vitro antitumor activity comparable or superior to doxorubicin against the human ovarian tumor cells (SK-OV-3) and the human CNS cells (XF 498). The IC(50) value for compound 9e was 0.06 microM against the human CNS cells (XF 498), which was 2.6 times higher than that (0.16 microM) of doxorubicin. In addition, the X-ray crystallographic analysis of two phenazinedione derivatives (9b,c) showed clearly the exact position of the nucleophilic substitution of 6,7-dichloro-5,8-quinolinedione.

A new series of DNA binding 5,10,15-tri(N-methyl-4-pyridiniumyl)porphyrin (TrisMPyP)-platinum(II) conjugates was synthesized, in which different spacer ligands were used for appropriate coordination to platinum(II) complexes. Compound 9b exhibited in vivo antitumor activity (T/C%, 294) superior to cisplatin (T/C%, 184) against the leukemia L1210 cell line.

3′- N -Substituted-3′- N -debenzoylpaclitaxel analogues were synthesized and investigated for their 3-D QSAR by using comparative molecular field analysis (CoMFA). The CoMFA model obtained from receptor(microtubule)–paclitaxel binding structure displays an excellent predictive power to forecast the biological activity of new 3′- N -substituted-3′- N -debenzoylpaclitaxel analogues as well as the ability to explain the activity of the known paclitaxel analogues. The cross-validated r 2 cv values of the selected models are 0.835 and 0.616 for A549 and SK-OV-3, respectively, and the non-cross-validated r 2 ncv values of them are 0.992 and 0.974.

We report a series of phenyl substituted pyridazin-3-ones substituted with morpholino-pyrimidines. The SAR of the phenyl was explored and their c-Met kinase and cell-based inhibitory activity toward c-Met driven cell lines were evaluated. Described herein is a potent c-Met inhibitor by structural modification of the parent morpholino-pyridazinone scaffold, with particular focus on the phenyl and pyrimidine substituents.

Synthesized 6-arylamino-5,8-quinolinediones 4a-4j and 6-chloro-7-arylamino-5,8-isoquinolinediones 5a-5g were evaluated for effects on NAD(P)H: quinone oxidoreductase (NQO1) activity with the cytosolic fractions derived from cultured human lung cancer cells and their cytotoxicity in cultured several human solid cancer cell lines. The 5,8-quinolinediones 4 and 5,8-isoquinolinediones 5 affected the reduction potential by NQO1 activity and showed a potent cytotoxic activity against human cancer cell lines. The tested compounds 4a, 5c, 5f, and 5g were considered as more potent cytotoxic agents. The compounds 4d, 5b, 5c, 5e and 5g were comparable modulators of NQO1 activity.

Synthesized 5-arylamino-2-methyl-4,7-dioxobenzothiazoles 3a-3o were evaluated for modulation of NAD(P)H: quinone oxidoreductase (NQO1) activity with the cytosolic fractions derived from cultured human lung cancer cells and their cytotoxicity in cultured several human solid cancer cell lines. The 4,7-dioxobenzothiazoles affected the reduction potential by NQO1 activity and showed a potent cytotoxic activity against human cancer cell lines. The tested compounds 3a, 3b, 3g, 3h, 3n and 3o were considered as more potent cytotoxic agents, and comparable modulators of NQO1 activity.

2-Methyl-1-substituted-imidazo[4,5- g ]quinoline-4,9-diones and 7,8-dihydro-10 H -[1,4]oxazino -[3′,4′:2,3]imidazo[4,5- g ]quinoline-5,12-dione ( 19 ) derivatives have been synthesized from 6,7-dichloro-5,8-quinolinedione for developing the new anticancer drugs. Our study on the cytotoxicity of imidazoquinolinedione derivatives has revealed that 7,8-dihydro-10 H -[1,4]oxazino-[3′,4′:2,3]imidazo[4,5- g ]quinoline-5,12-dione ( 19 ), a tetracyclic heteroquinone analogue, exhibited high cytotoxicity on human colon tumor cell (HCT 15) in vitro SRB assay. The IC 50 value of this compound was 0.026 μg/mL whereas those of doxorubicin and cisplatin were 0.023 μg/mL and 1.482 μg/mL, respectively. Meanwhile compounds 5 – 7 and 12 in the series of 1-substituted-imidazoquinolinediones showed relatively good activity on human brain tumor cell lines (XF 498).

The 3′- N -acyl- N -debenzoylpaclitaxel analogues 1a – d Download high-res image (174KB) Download full-size image Scheme 1 . Reagents and conditions: (i) DCC, toluene, 35°C, 2 h; (ii) c -HCl, then aq NaHCO 3 , EtOAc; (iii) RCOCl, pyridine; (iv) NH 4 OAc, MeOH-THF. were synthesized and evaluated on biological systems. Some of the analogues 1a – d exhibited higher cytotoxicities (up to 20-fold) and stronger abilities to induce apoptosis than paclitaxel. In an in vivo experiment against ip implanted B16 melanoma, the most cytotoxic compound 1b in vitro caused tumor growth inhibition more than paclitaxel.

Cinnamaldehydes and related compounds were synthesized from various cinnamic acids based on the 2'-hydroxycinnamaldehyde isolated from the bark of Cinnamomum cassia Blume. The cytotoxicity to human solid tumor cells such as A549, SK-OV-3, SK-MEL-2, XF498 and HCT15 were measured. Cinnamic acid, cinnamates and cinnamyl alcohols did not show any cytotoxicity against the human tumor cells. Cinnamaldehydes and related compounds were resistant to A549 cell line up to 15 micrograms/ml. In contrast, HCT15 and SK-MEL-2 cells were much sensitive to these cinnamaldehyde analogues which showed ED50 values 0.63-8.1 micrograms/ml. Cytotoxicity of the saturated aldehydes was much weak compared to their unsaturated aldehydes. From these studies, it was found that the key functional group of the cinnamaldehyde-related compounds in the antitumor activity is the propenal group.

A series of 5-hydroxy-4-quinolone ( 3 ) and 5-methoxy-4-quinolone ( 4 ) derivatives were synthesized as truncated acridone analogues and evaluated for antitumor and antiherpes activities. Among them 5-hydroxy-8-methoxy-quinolone showed potent antitumor activity (IC 50 = 17.7 μM for HL60) which was greater than that of acronycine.

A new series of 2,4-dianilino-5-fluoropyrimidine derivatives were designed and synthesized and their anaplastic lymphoma kinase (ALK) inhibitory activities were evaluated by biochemical and cell-based assays in order to discover a new ALK inhibitor. Most compounds synthesized showed good inhibitory activities against ALK and good cytotoxic activities in H3122 cell line. The best compound 6f showed good activity against wild-type ALK along with crizotinib-resistant mutant ALK, and it showed 6 times better activity in cell-based assay than crizotinib. Some SAR studies were performed by the comparisons of the activities between 6 and the designed-synthesized compounds.

The synthesis of bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines is described and their structure–activity-relationship to anaplastic lymphoma kinase (ALK) is presented. KRCA-0008 is selective and potent to ALK and Ack1, and displays drug-like properties without hERG liability. KRCA-0008 demonstrates in vivo efficacy comparable to Crizotinib in xenograft mice model.

Synthesis of novel arylsulfonylimidazolidinones 3 and 4 containing sulfonylurea pharmacophore and evaluation of their in vitro cytotoxicity against human cell lines were investigated. As a result, a series of 4-phenyl-1(N)-arylsulfonylimidazolidinones have been found to be the potential anticancer agent.

Phenolic compounds are prevalent as toxins or environmental pollutants, but they are also widely used as drugs for various purpose including anticancer agent. A novel biphenolic compound, bis(2-hydroxy-3-tert-butyl-5-methylphenyl)methane (GERI-BP002-A) was isolated from the fermentation broth ofAspergillus fumigatus F93 previously, and it has revealed cytotoxicity against human solid tumor cells. Its effective doses that cause 50% inhibition of cell growthin vitro against non-small cell lung cancer cell A549, ovarian cancer cell SK-OV-3, skin cancer cell SK-MEL-2 and central nerve system cancer cell XF498 were 8.24, 10.60, 8.83, 9.85 μg/ml respectively. GERI-BP002-A has also revealed cytotoxicity against P-glycoprotein-expressed human colon cancer cell HCT15 and its multidrug-resistant subline HCT15/CL02, and its cytotoxicity was not affected by P-glycoprotein. We have also tested cytotoxicities of structurally related compounds of GERI-BP002-A such as diphenylmethane, 1,1-bis(3,4-dimethylphenyl)ethane, 2,2-diphenylpropane, 2-benzylpyridine, 3-benzylpyridine, 4,4′-di-tert-butylphenyl, bibenzyl, 2,2′-dimethylbibenzyl,cis-stilbene,trans-stilbene, 3-tert-butyl-4-hydroxy-5-methylphenylsulfide, sulfadiazine and sulfisomidine for studying of structure and activity relationship, and from these data we could suppose that hydroxyl group of GERI-BP002-A conducted important role in its cytotoxicity.

Two xanthanolide sesquiterpene lactones, 8- epi-xanthatin (1) and 8- epi-xanthatin epoxide (2), isolated from the leaves of Xanthium strumarium (Compositae), demonstrated a significant inhibition on the proliferation of cultured human tumor cells, i. e., A549 (non-small cell lung), SK-OV-3 (ovary), SK-MEL-2 (melanoma), XF498 (central nervous system) and HCT-15 (colon) in vitro. They were also found to inhibit the farnesylation process of human lamin-B by farnesyltransferase (FTase), in a dose-dependent manner in vitro (IC 50 value was calculated as 64 and 58 microM, respectively). Due to the relatively high concentrations of 1 and 2 required to obtain an FTase inhibition as compared with those necessary for a cytotoxic effect on tumor cells, it remains unclear whether a relationship between these two activities exists.

Bioassay-guided chemical investigation of the stem bark of Melia azedarach var. Japonica has led to a new limonoid, 12-hydroxyamoorastatone along with two known limonoids 12-hydroxyamoorastatin and 12-acetoxyam- oorastatin. The structure of the new compound followed from spectral data and the stereochemistry was determined by NOE experiment on the di- p -bromobenzoate. All three compounds exhibited significant cytotoxicites against five human tumour cell lines.

A series of hydroxybenzoxazole derivatives was synthesized, and their c-Met kinase inhibitory activity was evaluated. Described herein is a potent c-Met inhibitor by structural modification of the parent benzoxazole scaffold, with particular focus on the hydroxyl substituent of the benzoxazole moiety.

Synthesis of novel arylsulfonylimidazolidinones 3 and 4 containing sulfonylurea pharmacophore and evaluation of their in vitro cytotoxicity against human cell lines were investigated. As a result, a series of 4-phenyl-1(N)-arylsulfonylimidazolidinones have been found to be the potential anticancer agent.

6-Chloro-7-arylamino-5,8-isoquinolinediones were newly synthesized and evaluated for in vitro cytotoxic activities against five human solid tumor cell lines. Among them, 5b, 5c and 5d exhibited potent activities against the cell lines HCT-15 and SK-MEL-2.

Benzofuroquinolinediones (7c and 7d) were synthesized by base-catalyzed condensation of dichloroquinolinediones with phenolic derivatives. Their dialkylaminoalkoxy derivatives (8i-8p) were prepared by reaction with various dialkylaminoalkyl chlorides. The cytotoxicity of the synthesized compounds was evaluated against eight types of human cancer cell lines, and their topoisomerase II inhibition was assessed. In general, the cytotoxicity of benzofuroquinolinediones (8i-8p) was similar or superior to that of doxorubicin and showed more potent inhibitory activity than naphthofurandiones (8a-8h). Also, most of the compounds exhibited excellent topoisomerase II inhibitory activity at a concentration of 5 microM and two compounds, 8d and 8i, showed IC50 values of 1.19 and 0.68 microM, respectively, and were much more potent than etoposide (IC50=78.4 microM), but similar to doxorubicin (IC50=2.67 microM). However their inhibitory activity on topoisomerase I was lower, and 8d and 8i showed IC50 values of 42.0 and 64.3 microM, respectively.

Jineol (1), a new quinoline alkaloid, was isolated from the centipede Scolopendra subspinipes, and its structure was elucidated by 2D NMR experiments. Jineol exhibited modest cytotoxic activity in vitro against the growth of human tumor cell lines: A-549, SKOV-3, SK-Mel-2, XF-498, and HCT-15 cells.

The cytotoxicity-directed fractionation of MeOH extract ofTerminalia chebula fruits led to the isolation of three hydrolyzed tannins and a related compound, gallic acid(I), 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose(II), chebulagic acid(III) and chebulinic acid(IV), as active principles. They were shown to exhibit moderate cytotoxicity against cultured human tumor cell lines including A-549, SK-OV-3, SK-MEL-2, XF-498 and HCT-15in vitro.

3-Ethoxycarbonyl-3-methyl-1N-substrituted-2,3-dihydro-pyridin[2,3-f]indole-2,4,9-trione [9(a-d)] and 3-ethoxycarbonyl-3-methyl-N-substrituted-2,3-dihydro-benz[f]indole-2,4,9-trione [10(a-i)] derivatives were synthesized from 7-chloro-6-(1,1-diethoxycarbonyl-ethyl)-5,8-quinolinedione (7) and 2-chloro-3-(1,1-diethoxycarbonyl-ethyl)-1,4-naphthoquinone (8), respectively, using a variety of alkyl- and arylamines. The cytotoxic activities of the synthesized compounds were evaluated by a Sulforhodamine B (SRB) assay against the following tumor cell lines: A459 (human non-small cell lung), SK-OV-3 (human ovarian), SK-MEL-2 (human melanoma), XF498 (human CNS), and HCT 15 (human colon). Almost all the derivatives mentioned above had a more potent cytotoxic effect against SK-OV-3 than etoposide. In particular, 3-ethoxycarbonyl-3-methyl-N-(4-aminophenyl)-2,3-dihydro-benz[f]indole-2,4,9-trione (10h) exhibited greater activity against all the tumor cell lines, and its cytotoxic effect against SK-OV-3 was especially higher than doxorubicin.

A series of 4-(N-imidazol-2-ylmethyl)aminobenzopyran analogues, originally designed as KATP openers for ischemic diseases, showed antiangiogenic properties through the inhibition of HUVEC tube formation. Especially one of p-Cl substituted analogues (4c) completely inhibited HUVEC tube formation at 10 μM. The compound 4c significantly inhibited tumor growth by 52% on A549 (human non small cell lung carcinoma) in nude mice xenografts without any significant side effects.

Four flavonoid glycosides, flavaprin (7), evodioside B (8), vitexin (11), and hesperidin (12), as well as the coumarins bergapten (1), xanthotoxin (2), and isopimpinellin (3), the lignan simplexoside (10), the steroids beta-sitosterol (4) and daucosterol (5), the limonoids isolimonexic acid (6) and limonin (9), and uracil (13) and myo-inositol (14) have been isolated from Euodia daniellii. The structures of these compounds were established from spectral data. Among the isolates, bergapten showed cyclooxygenase-2 inhibitory activity with an IC50 value of 6.2 microg/ml. Flavonoids isolated from this plant exhibited no cytotoxic activity against the human tumor cell lines, A549, SKOV-3, SKMEL-2, XF498, and HCT15.

Thirteen kinds of naturally occurring or derivatised triterpenes, reported to have an antitumoral property, were reinvestigated on the basis of their direct cytotoxicity or the inhibitory activity on cell growth against five kinds of cultured human tumor cells,i. e., A-549, SK-OV-3, SK-MEL-2, XF498 and HCT15,in vitro. Ursonic acidIII, betulinic acidVIII, betulonic acidX and glycyrrhetinic acidXI were exhibited a marked inhibition on cell growth.

A series of 3′- N -acyl-paclitaxel analogues 1a – v were synthesized and their cytotoxicities in vitro against several human tumor cell lines examined. It has been shown that distinct correlation between activity and N -acyl-substituent. The appropriate size of N -acyl group was indispensable for cytotoxicity, and moreover, the presence of β-substituted conjugated double and triple bond to N -carbonyl generally resulted in increase of cytotoxicities.

We report upon the synthesis of the following derivatives: N-substituted-pyridino[2,3-f]indole-4,9-dione, and 6-(alpha-diethoxycarbonyl-methyl)-7-substituted-amino-quinoline-5,8-dione, which contain the active quinoline-5,8-dione (VII) moiety. The cytotoxic activities of these compounds have been tested in SRB (SulfoRhodamine B) assays against the cancer cell lines of A-549 (human lung cancer), SK-MEL-2 (human melanoma cancer), SK-OV-3 (human ovarian cancer), XF-498 (human brain cancer) and HCT 15 (human colon cancer). The compound, N-benzyl-3-ethoxycarbonyl-2-hydroxy-pyridino[2,3-f]indole-4,9-dione (A-9), also showed higher activity than cis-platin. The highest level of cytotoxic activity in these human tumor cell lines was observed in the compound 6-(alpha-diethoxycarbonyl-methyl)-7-(2-methyl-phenylamino)-quinoline-5,8-dione (B-3).

Costunolide, a germacrane sesquiterpene lactone isolated from the stem bark of Magnolia sieboldii demonstrated a significant inhibition upon the farnesylation process of human lamin-B by farnesyl-proteintransferase (FPTase), in a dose dependent manner in vitro (IC50 value was calculated as 20 microM). It was also found to exhibit an inhibition upon the proliferation of cultured human tumor cells, i.e., A549 (non small cell lung), SK-OV-3 (ovary), SK-MEL-2 (melanoma), XF498 (central nerve system) and HCT-15 (colon), in vitro.

Bioassay-guided fractionation of Crataegus pinnatifida (Rosaceae) gave two cytotoxic ursane-type triterpenes which were identified as uvaol (1) and ursolic acid (2) by physicochemical and spectroscopic methods. 3-Oxo-ursolic acid (3) was synthesized from ursolic acid (2) by Jones method. The cytotoxic activities of these compounds were tested against murine L1210 and human cancer cell lines (A549, SK-OV-3, SK-MEL-2, XF498, and HCT15) in vitro. Compounds 1 and 2 showed moderate cytotoxicities against L1210, whereas they showed weak activities against human cancer cell lines. However, compound 3 exhibited potent cytotoxic activities both in murine and in human cancer cell lines.