Synthesis of 4β-triazole-podophyllotoxin derivatives by azide-alkyne cycloaddition and biological evaluation as potential antitumor agents

A representative synthetic process of derivatizing the natural product podophyllotoxin utilizing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) is described including molecular design, reaction optimization and X-ray structure confirmation. Evaluation of cytotoxicity against human cancer cell lines (Hela, K562 and K562/A02) using MTT assay proves that these triazole derivatives have good antitumor activities. High activities toward the drug resistant K562/A02 cell line reveal promising future for these derivatives. The rarely prepared 1,5-disubstituted triazole isomers, which would be omitted by the "click chemistry", were found to have superior cytotoxicities to that of the 1,4-disubstituted isomers.     

2,3-Disubstituted 8-arylamino-3H-imidazo[4,5-g]quinazolines: a novel class of antitumor agents

A series of 2,3-disubstituted 8-arylamino-3H-imidazo[4,5-g]quinazolines were synthesized and evaluated for their cytotoxic activity in vitro against five human cancer cell lines (human lung carcinoma cell line: A549, human leukemia cell lines: K562 and Molt-4, human prostate cancer cell line: PC-3, human breast carcinoma cell line: MDA-MB-231). Most of these compounds show potent activity against these tumor cell lines, especially against the A549 cell line. The cell cycle analysis was also studied by flow cytometry measurement on A549 cell line.     

Synthesis and biological activity of alpha-bromoacryloyl lexitropsin conjugates

The design, synthesis and biological evaluation of lexitropsins bearing mixed heterocyclic and benzoheterocyclic moieties and tethered to an alpha-bromo acrylic moiety acting as alkylating moiety are reported, and structure-activity relationships determined. With respect to antiproliferative activity against L1210 and K562 cells, compounds 7 and 10 showed the greatest potency, while compounds 4 and 5 exhibit the lowest activity. Among the synthesized compounds 4-12, the derivative 10 was found to be the most potent member of this class and it is 70-fold more active than the bis-pyrrole counterpart 3 against L1210 cell line. In addition, the cytotoxicity of derivatives 5-12 against KB cells and the influence of different glutathione (GSH) concentrations on the cytotoxic effects was also investigated.     

Synthesis and antiproliferative activities of isoindigo and azaisoindigo derivatives

In the course of structure-activity relationship studies, diversely substituted 1-(beta- d-acetylatedglucopyranosyl)isoindigo derivatives were prepared from indolines. New 7'-azaisoindigo analogues were also synthesized by coupling a glycosylated isatine and a 7-azaindolin-2-one derivative. Compounds containing a 7'-azaisoindigo framework have never been described before. To get an insight into the substitution pattern required for the best biological potencies, their antiproliferative activities were evaluated toward a human buccal carcinoma cell line (KB) and two human myeloid leukaemia cell lines (K562, HL60).     

Antiproliferative effect of Baylis-Hillman adducts and a new phthalide derivative on human tumor cell lines

In this work we report our results concerning the study on the in vitro antiproliferative activity of 18 Baylis-Hillman adducts and some derivatives against a panel of humor tumor cell lines. A brief qualitative structure-activity relationship study indicated that carbon-carbon double bond and the presence of an electron-withdrawing substituent at the aromatic ring are essential for the activity. A quinoline-phthalide derivative has exhibited a potent effect on the proliferation of all cell lines. It is interesting to note their special cytotoxic activity against NCIADR cell line.     

Synthesis and antiproliferative activity of aryl- and heteroaryl-hydrazones derived from xanthone carbaldehydes

In order to explore the antiproliferative effect associated with the xanthone framework, several arylhydrazonomethyl derivatives were synthesized from various isomeric 1,3-dihydroxyxanthone carbaldehydes. Variation in the position of the aldehydic function led to three sets of compounds, bearing the hydrazonomethyl chain at positions 5, 6 or 7 on the xanthone nucleus, respectively. The antiproliferative effect of the compounds was evaluated in vitro using the MTT colorimetric method against two human cancer cell lines (MCF-7, breast adenocarcinoma, and KB 3.1, squamous cell oral carcinoma) for two time periods (24 h and 72 h). Among the series, four compounds exhibited interesting growth inhibitory effects against both the cell lines, with IC(50) values in the micromolar concentration range. When compared with doxorubicin, the xanthone derivatives showed moderate cytotoxic effects. Surprisingly, unlike doxorubicin, these compounds displayed no significant time-dependent change in the concentration causing 50% inhibitory effect in proliferation. This unusual cytotoxicity profile led to the hypothesis that these molecules could be endowed with a mechanism of action distinct to that of doxorubicin.     

Synthesis of amide and urea derivatives of benzothiazole as Raf-1 inhibitor

A series of amide and urea derivatives of benzothiazole have been synthesized and evaluated for their antiproliferative profile in human SK-Hep-1 (liver), MDA-MB-231 (breast), and NUGC-3 (gastric) cell lines. Among them, compounds 1-2, 16-18, 23, and 25-26 had potent to moderate inhibitory activities. Further these compounds were investigated for their ability to inhibit Raf-1 activity.     

In vitro and in vivo antitumor activity of platinum(II) complexes with thiosemicarbazones derived from 2-formyl and 2-acetyl pyridine and containing ring incorporated at N(4)-position: synthesis, spectroscopic study and crystal structure of platinum(II) complexes with thiosemicarbazones, potential anticancer agents

Reactions of thiosemicarbazones of 2-formyl and 2-acetyl pyridine and containing an azepane ring (hexamethyleneiminyl ring) incorporated at N(4)-position, HL(1) (1) and HL(2) (2) with platinum(II) afforded the complexes, [Pt(L(1))Cl] (3) and [Pt(L(2))Cl] (4). Characterization of the compounds was accomplished by means of elemental analysis and spectroscopic techniques NMR, UV-vis and IR spectroscopy. The single-crystal X-ray structure of complex [Pt(L(2))Cl] (4) shows that the ligand monoanion coordinates in a planar conformation to the metal via the pyridyl N atom, the imine-N atom, and thiolato S-atom. Compounds 1-4 have been evaluated for antiproliferative activity in vitro against three human cancer cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma) and a mouse L-929 (a fibroblast-like cell line cloned from strain L). Ligand 2 exhibited high activity as anticancer agent against all four cancer cell lines, while ligand 1 exhibited selectivity against MCF-7, L-929 cell lines and complex 4 against A-549, T-24 cancer cell lines. Also, the acute toxicity and antitumor activity were evaluated on leukemia P388-bearing mice. Complex 3 afforded five to six cures against leukemia P388. The in vivo results of the antitumor activity show the two platinum complexes as very effective chemotherapeutic antileukemic agents.     

Synthesis and cytotoxic activity of new alkyl[3-(2-chloroethyl)ureido]benzene derivatives

Several alkyl[3-(2-chloroethyl)ureido] (CEU) benzene derivatives were prepared as potential anticancer agents. These new compounds were readily prepared in good yields by addition of anilines to 2-chloroethylisocyanate. Their cytotoxic activity was evaluated on human breast cancer (MDA-MB-231), human colon adenocarcinoma (LoVo) and mouse lymphocytic leukemia (P388D₁) tumor cell lines. Several new CEUs were significantly more cytotoxic than the nitrogen mustard chlorambucil. The biological activity of these aromatic urea derivatives seems to be related to the nature and position of the alkyl substituents on the aromatic ring. Substitution by branched alkyl groups on position 4 of the aromatic ring led to cytotoxic molecules which are up to 5 times more potent than the standard chlorambucil.     

Synthesis and biological activities of indolocarbazoles bearing amino acid residues

Three indolocarbazole compounds bearing a tripeptide or a lysine group attached to one of the indole nitrogens via a propylamino chain and two rebeccamycin derivatives bearing a lysine residue on the sugar moiety were synthesised with the aim of improving the binding to DNA and the antiproliferative activities. Four tumour cell lines, from murine L1210 leukemia, human HT29 colon carcinoma, A549 non-small cell lung carcinoma and K-562 leukemia, were used to evaluate the cytotoxicity of the drugs. Their effects on the cell cycle of L1210 cells and their antimicrobial properties against two Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans were also investigated.     

Synthesis and in vitro antiproliferative activity of novel 1-benzhydrylpiperazine derivatives against human cancer cell lines

In order to explore the antiproliferative effect associated with the piperazine framework, several 1-benzhydrylpiperazine derivatives 8(a-d), 9(a-d) and 10(a-h) were synthesized. Variation in the functional group at N-terminal of the piperazine led to three sets of compounds, bearing the sulfonyl, amide and thiourea, respectively. Their chemical structures were confirmed by (1)H NMR, LCMS, IR and elemental analysis. The antiproliferative effect of the compounds were evaluated in vitro using the MTT colorimetric method against one normal cell line (NF-103 skin fibroblast cells) and four human cancer cell lines (MCF-7 breast carcinoma cell line, HepG-2 hepatocellular carcinoma cell line, HeLa cervix carcinoma cell line and HT-29 colon carcinoma cell line) for the time period of 24 h. Among the series, four compounds exhibited interesting growth inhibitory effects against all four cell lines.     

Synthesis and anticancer activity of lavendustin A derivatives containing arylethenylchromone substituents

2-Styrylchromones, which are relatively scarce in nature, have been reported to possess potent cytotoxicities on KB cell line. Lavendustin A, a metabolite of Streptomyces griseolavendus, has been shown to inhibit a growth of A431 cell line. Accordingly, a series of compounds 3a-g having structural features of styrylchromones and lavendustin A were synthesized and evaluated for cytotoxicity using SRB assay on four tumor cell lines. Compounds 3a-g were synthesized by the condensation of 2-methylchromone derivative 7 with several aromatic aldehydes. Among synthesized, compound 3e showed the significant cytotoxic activity on HCT-15 cell line with IC(50) values of 7.17 microg/ml indicating that lavendustin A derivatives containing 2-arylethenylchromone ring have a potential in anti-tumor application.     

Synthesis and induction of G0-G1 phase arrest with apoptosis of 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4(3H)-one

The multistep synthesis of 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4(3H)-one 15 has been carried out. The compound showed antiproliferative and apoptotic effects against K562, K562-R (imatinib mesilate resistant), HL60 and multidrug resistant (MDR) HL60 cell lines. Compound 15 showed a pro-apoptotic activity against HL60 and K562 resistant cell lines markedly higher than etoposide and busulfan, respectively. Flow cytometry studies carried out on K562 cells allowed to establish that 15 induces G0-G1 phase arrest followed by apoptosis.     

Novel pentamidine derivatives: synthesis, anti-tumor properties and polynucleotide-binding activities

Novel amidino-substituted conformationally restricted derivatives of pentamidine were synthesized and their antiproliferative activity against several human cancer cell lines determined. It was found that introduction of furandicarboxamide core moiety (9, 10) increases antiproliferative activity as well as selectivity against certain tumor cell lines in comparison with amidino-substituted furan-mono-carboxamide (5, 6). Unlike the furan series where iso-propyl substituted amidine (10) exhibits more potent overall antiproliferative activity and selectivity toward certain cell lines, the same was found for unsubstituted amidines in pyridine series. Amongst all tested compounds the compound 10 is the only one that possesses antiproliferative activity against SW 620 cell line (4 μM). Spectroscopic studies of the interactions of prepared diamidines with double-stranded DNA and RNA polynucleotides show that all compounds preferentially bind into the minor groove of DNA, while most of them intercalate into RNA. The structure-dependant biological activity and the lack of DNA/RNA selective binding suggest that the mechanism of action of the here-presented compounds is controlled not only by the interactions with cellular nucleic acids, but also with other more specific protein targets.     

Design, synthesis, and biological evaluation of novel γ-carboline ketones as anticancer agents

A series of novel γ-carboline ketones were designed, synthesized and evaluated for their cytotoxic activity in vitro against six human cancer cell lines (A549, SGC, HCT116, MCF-7, K562 and K562R). Biological evaluation revealed that almost all of the new compounds displayed moderate to potent cytotoxic activities against the tested cells. Among them, seven of the fourteen new compounds show more potent cytotoxic activities against K562R cell line than that of the positive control, taxol. Primary mechanism research on the most potent compound 6f indicated that it was a potent tubulin polymerization inhibitor, with IC₅₀ value of 4.3 μM, equivalent to that of CA-4, and arresting cell cycle in G₂/M phase.     

Synthesis and antitumor activity of cis-dichloroplatinum(II) complexes of 1-(2-aminophenyl)-1,2,3,4-tetrahydroisoquinolines

Fifteen cis-dichloroplatinum complexes (5a-5o) were synthesized by treatment of 1-(2-aminophenyl)-1,2,3,4-THIQs (4a-4o) with K(2)PtCl(4). The antitumor activity of these compounds was examined against four different human tumor cell lines. Their structure-activity relationships for antitumor activity are reported. All of these compounds exhibited activity against MCF-7 cell line and showed good activity against WiDr cell line except 5c and 5f. On the other hand, compounds 5j and 5o are more active than the other compounds against Hepa59T/VGH cell line. The electron-donating group at the 6-position of isoquinoline ring seems to decrease the antitumor activity and the chloro substituent at the C-4 position of the aniline ring shown the highest potency. The "trans influence" dominates the control of the stability of [1-(2-aminophenyl)-1,2,3,4-THIQ]dichloroplatinums(II).     

Design and synthesis of new pyranoxanthenones bearing a nitro group or an aminosubstituted side chain on the pyran ring. Evaluation of their growth inhibitory activity in breast cancer cells

Some new 2,6-disubstituted pyrano- and 1,2-dihydropyrano[2,3-c]xanthen-7-ones have been synthesized and their antiproliferative activity has been evaluated against MDA-MB-231 breast cancer cells. The antiproliferative activity evaluation of the compounds provided evidence that a dimethylamino substituted side chain and the presence of 1,2 double bond play a key role in cell growth inhibition. Among the tested derivatives the 6-dimethylaminoethylamino-2-nitropyranoxanthenone analogue possessed a significant inhibitory effect in a wide range of concentrations.     

Synthesis, hypoxia-selective cytotoxicity of new 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives

We reported the synthesis, hypoxic cytotoxic activities and selectivities of 18 new 3-(alkoxymethylamino)-1,2,4-benzotriazine 1,4-dioxides. The synthesized compounds were screened in vitro against 5 cell lines: K562, SMMC-7721, A549, PC-3 and KB in hypoxia and in normoxia. Some of them showed higher or similar cytotoxic activity when compared to tirapazamine. Physico-chemical study showed the positive correlation between hypoxic activity and lipophilicity within a certain range. Preliminary mechanism study on the potent derivatives 4b, 4l and 4m indicated that the cytotoxic activities of these compounds might be mediated by inducing apoptosis.     

Syntheses and cytotoxicities of the analogues of the taxoid brevifoliol

Seven novel brevifoliol analogues have been synthesized by coupling brevifoliol and 2-monosubstituted-4-phenyl-1,3-oxazolidine carboxylic acid after removal of the protecting group with acid treatment. Brevifoliol and its synthesized analogues were tested for their cytotoxic activities against four different human cancer cell lines, oral (KB), breast (MCF-7), colon (CaCO2) and liver (HepG-2) as determined by MTT assay. The C-13 oxidized brevifoliol retained significant activity. Out of the seven analogues synthesized, C-13 oxidized brevifoliol-5-[N-tert-butoxycarbonyl amino-(2'R,3'S)-3'-phenyl isoserine] analogue was interesting as it exhibited selective and potent cytotoxicity against liver cancer cell line predominantly.     

Structure-cytotoxicity relationship in a series of N-phosphorus substituted E,E-3,5-bis(3-pyridinylmethylene)- and E,E-3,5-bis(4-pyridinylmethylene)piperid-4-ones

In order to give further insight on the influence of the aromatic ring nature and the presence of the phosphorus substituent at the piperidone nitrogen atom of E,E-3,5-bis((hetero)arylidene)piperid-4-ones on their antitumor properties, a series of phosphorus substituted E,E-3,5-bis(pyridinylmethylene)piperid-4-ones bearing either 3-pyridine or 4-pyridine rings was obtained. Novel NH-3,5-bis(pyridinylmethylene)piperid-4-ones 1a,b were converted into the corresponding N-phosphorylated derivatives 3a-c, 4a-c differing in the substitution at the phosphorus atom (amidophosphates and amidophosphonates), via direct phosphorylation while N-(ω-phosphorylalkyl)-substituted compounds 8a-c were obtained via aldol-crotonic condensation of preformed N-phosphorylalkyl substituted piperidones with the corresponding pyridinecarboxaldehyde. The cytotoxicity screen has revealed that phosphorylated compounds based on E,E-3,5-bis(4-pyridinylmethylene)piperid-4-one framework displayed higher inhibitory properties toward Caov3, A549, KB 3-1 and KB 8-5 human carcinoma cell lines comparing with their analogues with 3-pyridine rings. Introduction of the phosphorus moiety substantially increased the antitumor properties in the case of E,E-3,5-bis(3-pyridinylmethylene)piperid-4-ones derivatives but this influence less pronounced for more active analogues bearing 4-pyridinyl rings. Most of the compounds tested are potent against multi-drug resistant cell line KB 8-5 affording some guidelines for the search of perspective drug-candidates among phosphorus substituted E,E-3,5-bis((hetero)arylidene)piperid-4-ones.