Synthesis of 1-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)semi-carbazides and their transformation into 4-chloro-2-mercapto-N-(4,5-dihydro-5-oxo-4-phenyl-1H-1,2,4-triazol-3-yl)benzenesulfonamides as potential anticancer and anti-HIV agents

Synthesis of a series of 1-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)semicarbazides (6-16) and 4-chloro-2-mercapto-N-(4,5-dihydro-5-oxo-4-phenyl-1H-1,2,4-triazol-3-yl)benzenesulfonamides (17-22) were reported. Compounds 7-9, 17, 19-22 were tested at the US National Cancer Institute for their in vitro anticancer and anti-HIV activities. Results of anticancer screening showed moderate activity of 21 and 22, while 19 was found to have encouraging anti-HIV activity at EC(50) = 28.8 microM.     

2-Amino-3-cyano-4-(5-arylisoxazol-3-yl)-4H-chromenes: synthesis and in vitro cytotoxic activity

A new series of 4-aryl-4H-chromenes bearing a 5-arylisoxazol-3-yl moiety at the C-4 position were prepared as potential anticancer agents. The in vitro cytotoxic activity of the synthesized compounds was investigated against a panel of tumor cell lines including MCF-7 (breast cancer), KB (nasopharyngeal epidermoid carcinoma), Hep-G2 (liver carcinoma), MDA-MB-231 (breast cancer), and SKNMC (human neuroblastoma) using the MTT colorimetric assay. Doxorubicin, a well-known anticancer drug, was used as positive standard drug. Among the synthesized compounds, the 5-(3-methylphenyl)isoxazol-3-yl analog (7j) showed the most potent cytotoxic activity against all five human tumor cell lines.     

In vitro screening of dry fruit extracts of Piper attenuatum for antioxidant and anticancer activity

Indian traditional medicinal plant Piper attenuatum (Buch-Ham) has been investigated for its antioxidant and anticancer activity. Three extracts were prepared using ethyl acetate, ethanol and methanol. In vitro antioxidant activity was performed by ABTS {2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)} free radical scavenging method. All three extracts reduced the free radicals produced by ABTS in a concentration-dependent manner which could be compared to the standard (gallic acid). Invitro anticancer activity of all extracts was carried out by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay method against MCF7 (Michigan Cancer Foundation-7) cell lines. None of the extract showed anticancer activity when compared with the standard (mitomycin C) indicating that P. attenuatum is deprived of antiproliferative or cytotoxic components.     

Preparation and biological evaluation of 6/7-trifluoromethyl(nitro)-, 6,7-difluoro-3-alkyl (aryl)-substituted-quinoxalin-2-ones. Part 3.

A new series of quinoxalinones 6/7-trifluoromethyl or nitro- and 6,7-difluoro substituted bearing various side-chains (alkyl, halogenoalkyl, benzyl and phenyl groups) at C-3 of the ring system was synthesized and submitted to preliminary in vitro evaluation for antibacterial, antifungal, antimycobacterial, anticancer and anti-HIV activities. Results of these screenings showed that compounds 23-28 exhibited a good inhibition activity against various strains of Candida. Compound 24 showed also an interesting in vitro anticancer activity.     

Synthesis of some new fluorine bearing trisubstituted 3-thioxo-1,2,4-triazin-5-ones as potential anticancer agents.

In a search for new anticancer agents fluorine bearing trisubstituted 3-thioxo-1,2,4-triazin-5-ones (2-12) have been prepared and characterized by their elemental analysis, UV, IR and 1H-NMR spectral data. The in vitro anticancer activity of all the compounds has been determined. Compounds 3 and 7 showed a moderate activity against Leukemia/Lymphoma, Small/Non small Cell Lung, Colon carcinoma and Melanoma Cells.     

Quinoxaline chemistry. Part 13: 3-Carboxy-2-benzylamino-substituted quinoxalines and N-[4-[(3-carboxyquinoxalin-2-yl) aminomethyl]benzoyl]-L-glutamates: synthesis and evaluation of in vitro anticancer activity

Among a new series of 28 3-carboxy or carbethoxy quinoxalines bearing a substituted benzylamino or N-[4-(aminomethyl)benzoyl]glutamate group on position 2 of the ring and various substituents at C-6, 7 positions, 21 were selected at the National Cancer Institute for evaluation of their in vitro anticancer activity. The results obtained seem to confirm that the carboxy or carbethoxy group on position 3 is not helpful, with a few exceptions, for the anticancer activity.     

Specific anticancer activity of a new bisabolane sesquiterpene against human leukemia cells inducing differentiation in vitro

A bisabolane sesquiterpene, rel-(1S,4R,5S,6R)-4,5-diacetoxy-6- [(R)-5-hydroxy-1,5-dimethylhex-3-enyl]- 3-methylcyclohex-2-enyl (Z)-2-methylbut-2 -enoate, which was newly isolated from the roots of Leontopodium longifolium, presented specific anticancer activity against human leukemia HL-60 cells, but did not inhibit proliferation of human hepatoma SMMC-7721 cells and human normal hepatocytes L02 cells. Nitroblue tetrazolium (NBT) reduction, phagocytosis of latex beads, and cell electrophoresis all demonstrated that this bisabolane sesquiterpene presented its anticancer activity against human leukemia HL-60 cells in vitro via inducing cell differentiation. Our results may have implications for treatment of human leukemia with the sesquiterpene.     

10-羟基喜树碱衍生物的合成及体外抑制肿瘤活性

目的寻找高效低毒的喜树碱类抗肿瘤新药。方法合成7个喜树碱衍生物（3~9），经¹HNMR，IR，MS分析确证了所合成化合物的结构，经MTT法筛选了对宫颈癌Hela、肝癌BEL-7402、胃癌7901和大肠癌CCL-187瘤株的体外抑制肿瘤活性。结果7个化合物分别对前三种瘤株有效，其中化合物4对前三种瘤株均有较好的体外抑制肿瘤细胞活性，尤其对宫颈癌Hela细胞的抑制活性大于10-羟基喜树碱。结论该类化合物的抗癌活性值得进一步研究。     

Antimitotic agents: ring analogues and derivatives of ethyl [(S)-5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7- yl]carbamate.

The synthesis of ring analogues and derivatives of the S isomer of ethyl [5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 - yl[carbamate, (S)-1, a potent antimitotic agent with anticancer activity, was directed toward the determination of the contribution of several structural features of this compound to biological activity. Replacement of the 5-amino with a 5(6H)-oxo group and either transposing the 6-ring nitrogen to or incorporation of a ring nitrogen at the 8-position caused a significant decrease in in vitro activity and destroyed in vivo activity. Although in vivo cytotoxicity was reduced, in vitro activity at higher doses relative to (S)-1 was retained by replacement of the 5-amino group with hydrogen and by expansion of the 1,2-dihydropyrazine to give a dihydro-1,4-diazepine ring.     

New potential anticancer agents based on the anthranilic acid scaffold: synthesis and evaluation of biological activity

The synthesis and anticancer activity of new compounds designed on the anthranilic acid scaffold are reported. The antiproliferative activity was assayed by the National Cancer Institute in established in vitro and in vivo anticancer experimental models. Structural variations based on the flufenamic acid motif afforded a series of (hetero)aryl esters of N-(2-(trifluoromethyl)pyridin-4-yl)anthranilic acid, which showed in vitro growth inhibitory properties against human tumor cell lines in nanomolar to low micromolar concentrations. The pyridinyl ester 25 exhibited very potent in vitro antiproliferative efficacy, with a chemosensitive profile showing a number of GI(50) values at concentrations lower than 10(-7) M in the full panel of human tumor cell lines. Compound 25 was also tested in vivo as a potential anticancer agent in the hollow fiber assay and in human tumor xenografts, showing moderate inhibitory properties. Analysis of biological activities and the COMPARE procedure was utilized to support putative biochemical mechanisms implicated with the antiproliferative activity.     

Quinoxaline chemistry. Part 14. 4-(2-Quinoxalylamino)-phenylacetates and 4-(2-quinoxalylamino)-phenylacetyl-L-glutamates as analogues--homologues of classical antifolate agents. Synthesis and evaluation of in vitro anticancer activity

Among a new series of 26 4-(3-substituted-2-quinoxalylamino)phenylacetates and 4-(3-substituted-2-quinoxalylamino)-phenylacetyl-L-glutamates, eight were selected at NCI for evaluation of their in vitro anticancer activity. The results obtained in comparison with the corresponding nor-compounds series seem to indicate that this type of homologation is not helpful.     

In vitro and in vivo growth inhibition and G1 arrest in human cancer cell lines by diaminophenyladamantane derivatives

We describe the discovery of a novel series of anticancer adamantane derivatives which induce G1 arrest in Colo 205 and HT 29 colon cancer cells. Seven adamantane derivatives were screened for their activity in vitro against 60 human cancer cell lines in the National Cancer Institute (NCI)'s Anticancer Drug Screen system. The relationships between structure and in vitro anticancer activity are discussed. 1,3-Bis(4-(4-amino-3-hydroxyphenoxy)phenyl)adamantane (1,3-DPA/OH/NH2) and 2,2-bis(4-(4-amino-3-hydroxyphenoxy)phenyl)adamantane (DPA) exhibited strong growth inhibitory on anticancer activities in vitro. The IC50s of 1,3-DPA/OH/NH2 (NSC-706835) and DPA (NSC-706832) were found to be < 3 microM against 45 (85%) and 48 (91%) cell lines, respectively. 2,2-Substituted adamantane derivatives exhibited stronger growth inhibition on anticancer activities in vitro than the corresponding 1,3-substituted analogs. Very strong growth inhibition of 2,2-bis(4-aminophenyl)adamantane (NSC-711117) was observed against two colon cancer lines (HT-29 and KM-12), one CNS cancer line (SF-295) and one breast cancer line (NCI/ADR-RES) with IC50 < 1.0 microM, i.e. 0.1, 0.01, 0.059 and 0.079 microM, respectively. In addition, we also examined the in vitro and in vivo effects of DPA on three human colon cancer cells. DPA-treated Colo 205 and HT-29 cells were arrested at G0/G1 as analyzed by flow cytometric analysis. The DPA-induced cell growth inhibition was irreversible after removal of DPA. The in vivo effect of tumor growth suppression by DPA was also observed on colon Colo 205 xenografts. No acute toxicity was observed after an i.p. challenge of DPA in ICR nude mice weekly. These results suggest that DPA appears to be a new potentially less toxic modality of cancer therapy.     

Quinoxaline chemistry. Part 12. 3-Carboxy-2[phenoxy]-6(7)substituted quinoxalines and N-[4-(6(7) substituted-3-carboxyquinoxalin-2-yl)hydroxy] benzoylglutamates. Synthesis and evaluation of in vitro anticancer activity

Thirty quinoxalines bearing a substituted phenoxy or hydroxybenzoylglutamate group on position 2, a carboethoxy or carboxy group on position 3 and a trifluoromethyl group on position 6 or 7 of the heterocycle were prepared in order to evaluate the in vitro anticancer activity. Screening over 21 compounds selected at the National Cancer Institute (Bethesda, MD) showed that only few derivatives exhibited a moderate growth inhibition activity on various tumor panel cell lines at 10(-4) molar concentration. The acid derivatives showed no growth inhibition activity. The results obtained in this series seem to indicate that in general carboxy or carboethoxy groups close to O-link with phenyl or benzoyl glutamates on position 2 are detrimental for anticancer activity.     

Novel prodrugs of tegafur that display improved anticancer activity and antiangiogenic properties

New and more potent prodrugs of the 5-fluorouracyl family derived by hydroxymethylation or acyloxymethylation of 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione (tegafur, 1) are described. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity, and anticancer activities in vitro and in vivo, superior to those of tegafur. 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1 H,3 H)-pyrimidinedione (tegafur, 1), the oral prodrug of 5-FU, has been widely used for treatment of gastrointestinal malignancies with modest efficacy. The aim of this study was to develop and characterize new and more potent prodrugs of the 5-FU family derived by hydroxymethylation or acyloxymethylation of tegafur. Comparison between the effect of tegafur and the new prodrugs on the viability of a variety of cancer cell lines showed that the IC50 and IC90 values of the novel prodrugs were 5-10-fold lower than those of tegafur. While significant differences between the IC50 values of tegafur were observed between the sensitive HT-29 and the resistant LS-1034 colon cancer cell lines, the prodrugs affected them to a similar degree, suggesting that they overcame drug resistance. The increased potency of the prodrugs could be attributed to the antiproliferative contribution imparted by formaldehyde and butyric acid, released upon metabolic degradation. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity and anticancer activities in vitro and in vivo, superior to those of tegafur.     

Antiproliferative activity of an aqueous mistletoe extract in human tumor cell lines and xenografts in vitro

The in vitro antiproliferative activity of an aqueous mistletoe extract (AME) with a defined content of bioactive mistletoe lectin (ML) was tested in 25 human tumor cell lines, including 20 solid and 5 hematological malignancies and 47 human tumor xenografts. The antiproliferative activity of AME was compared to that of the standard cytotoxic agent doxorubicin (CAS 23214-92-8, adriamycin, ADR) using the sulforhodamin B, propidium iodide and soft agar colony forming assays, respectively. AME was highly cytotoxic in solid human tumors with mean IC70 values in the range of 0.17-1 ng ML/ml (2.8-17 pmol bioactive ML). On a molar basis, AME was 3 to 4 logs more potent than ADR and showed differential cytotoxicity towards tumors of the breast, small cell and non-small cell lung, prostate and renal cell cancers. AME was also highly active in hematological malignancies with steep dose response curves resulting in mean IC70 values of 0.12 ng ML/ml (2 pmol). The acute lymphoblastic leukemia cell line HL-60 was the most sensitive, the histiocytic lymphoma cell line U937 the most resistant hematological malignancy. It is important to stress that AME did not induce a biologically relevant increase of cell proliferation in any of the tumor cell lines tested. Our data suggest that AME has in vitro antitumor profiles similar to those of classical anticancer agents. Clear dose-response relationships were found in all of the performed experiments and interesting differential cytotoxicity patterns were observed. Experiments with sensitive tumor types identified in these in vitro studies are currently ongoing in order to demonstrate the anticancer activity of AME in different animal tumor models.     

3-(3′-甲基-4′-取代苯基-1′,3′-丁二烯基)吲哚类衍生物的合成及其抗癌活性

目的　研究3-(3′-甲基-4′-取代苯基-1′,3′-丁二烯基)吲哚类衍生物的合成及其抗癌活性。方法　通过亲电取代、羟醛缩合、选择性还原、相转移Wittig反应和水解反应合成目的化合物,利用几种药理模型进行抗癌和抗炎活性筛选。结果　设计合成了11个3-(3′-甲基-4′-取代苯基-1′,3′-丁二烯基)吲哚化合物,均为新化合物。生物活性实验结果表明,化合物8对HL-60,HCT-8和Bel7402癌细胞株有效,且在浓度为10^-5mol·L^-1时,其抗炎抑制率可达100％。结论　化合物8显示了抑癌作用和抗炎活性,值得进一步研究。     

藤苦参素的体外抗肿瘤活性及其对癌细胞凋亡的作用

藤苦参（Streptocaulon griffithii Hook．f．）系萝摩科（Asclepiadaceae）马连鞍属（Streptocaulon Wight et Arn．）植物马连鞍的干燥根，又名古羊藤、南苦参、有毛老鸦嘴、虎阴藤、红藤、地苦参、小暗消、哈骂醒合（傣语）、哈骂不果（哈语）等，产于我国广西、贵州、云南等地。藤苦参为傣药经方雅叫哈顿散中的主治药之一，雅叫哈顿散已被中国药典2005版（一部）收载。张琳等研究了藤苦参的化学成分，未见有关藤苦参药理作用的研究报道。文献资料表明，藤苦参的同属植物多具有抗肿瘤作用。本实验对从藤苦参中分离得到的藤苦参素的体外抗肿瘤活性及其对癌细胞凋亡的作用进行研究。     

2,4-二氨基-5-甲基-6-取代苄氨基喹唑啉衍生物的合成及其抗疟和抗肿瘤作用

本文报道2,4-二氨基-5-甲基-6-取代苄氨基喹唑啉衍生物的合成及其抗疟和抗肿瘤活性。这类化合物由5-甲基-2,4,6-三氨基喹唑啉与相应的取代苯甲醛缩合成Schiff碱,然后经还原,甲酰化或亚硝化制得。经对伯氏鼠疟原虫(Plasmodium berghei)抑制性治疗筛选,有三个化合物Ⅳ_(2,5,6)剂量5mg/kg×4d抑制率为100%;体外抗肿瘤活性以Ⅱ_7和Ⅳ_8最强,对L1210白血病细胞株的IC_(50)分别为3.910×10~(-3)μg/ml和6.172×10~(-3)μg/ml,与MTX相当。     

Synthesis and antiproliferative activity in vitro of new propargyl thioquinolines

The series of new 3,4-disubstituted thioquinolines which possess one or two O, S, Se-propargyl groups has been synthesized on the basis of the reaction of thioquinanthrene with alkoxides. All the compounds obtained were tested for their antiproliferative activity in vitro against the cells of three human cancer cell lines: SW707 (colon cancer), T47D (breast cancer), and HCV29T (bladder cancer). Two compounds, 4-(3-hydroxypropoxy)-3'-propargylthio-3,4'-diquinolinyl sulfide (3) and 3-methylthio-4-propargylselenoquinoline (13) exhibited significant cytostatic activity (ID50 < 4 micrograms/ml) against the cells of all the human cancer lines used and are good candidates for further anticancer activity studies in vitro using a broad panel of human and murine cell lines and for in vivo preclinical screening in different mouse transplantable tumor models.     

In vitro growth inhibitory effects of cytochalasins and derivatives in cancer cells

The in vitro anticancer activity of eight natural cytochalasins and three hemisynthetic derivatives of cytochalasin B on six cancer cell lines was evaluated. The IC (50) in vitro growth inhibitory concentrations, as determined by an MTT colorimetric assay, ranged between 3 and 90 μM and did not relate to the intrinsic sensitivity of the cancer cell lines to proapoptotic stimuli. Structure activity relationship (SAR) analyses revealed that the presence of an unmodified hydroxyl group at C-7 of the perhydroisoinsolyl-1-one residue as well as the functionalities and the conformational freedom of the macrocycle are all important features for cytochalasin-mediated anticancer activities in vitro. Computer-assisted phase-contrast microscopy revealed two groups of cytochalasins, i.e., cytotoxic versus cytostatic ones. Our data open new possibilities for tuning cytochalasin targets and developing nontoxic, cytostatic cytochalasins to combat cancers associated with poor prognoses, such as those that display intrinsic resistance to proapoptotic stimuli.