Design, synthesis, single-crystal and preliminary antitumor activity of novel arenesulfonylimidazolidin-2-ones

Novel series of 1-(arenesulfonyl)imidazolidin-2-one (3a-i) and 1,3-bis(arenesulfonyl)imidazolidin-2-one (5a-i) have been synthesized and tested for their antitumor activity against 60 tumor cell lines taken from nine different organs. A significant inhibition for cancer cells was observed with series 5a-i compounds compared with the series 3a-i which showed a weak inhibition. Compounds 5a-i showed good inhibitory effect at the lung cancer HOP-92 and renal cancer CAKI-1 and UO-31 cell lines. Compound 5e showed remarkable broad-spectrum antitumor activity.     

Synthesis of novel psoralen analogues and their in vitro antitumor activity

New tetracyclic benzofurocoumarin (benzopsoralen) analogues were synthesized and their inhibitory effect on the growth of tumor cell lines was evaluated. The human tumor cell lines used were MDA MB231 (breast adenocarcinoma), HeLa (cervix adenocarcinoma) and TCC-SUP (bladder transitional cell carcinoma). The in vitro antitumor activity of the new benzopsoralens was discussed in terms of structure–activity relationship. Molecular docking studies with human-CYP2A6 enzymes were also carried out with the synthesized compounds in order to evaluate the potential of these compounds to interact with the heme group of the enzymes. The results have demonstrated that the linear compounds have the most pronounced activity against tumor cell lines and this might be related to the better accessibility that these compounds have to the active site in relation to the angular ones that have shown in the majority of the cases multiple binding poses in the active site of CYP2A6.     

Design, synthesis, and antitumor activity of new bis-aminomethylnaphthalenes

A new series of bis-aminomethylnaphthalenes were synthesized in satisfactory overall yield, through a simple synthetic strategy using reductive amination. The DNA binding properties of these compounds have been examined and compared to those of reference drugs using an UV spectroscopy method. The compounds were evaluated for their in vitro anticancer activity and some of them were studied in vivo. Compound 15 exhibited remarkable antitumor activity and represents a novel template for anticancer chemotherapy and can serve as a new lead compound.     

Design, synthesis, and docking studies of new 1,3,4-thiadiazole-2-thione derivatives with carbonic anhydrase inhibitory activity

A new series of 1,3,4-thiadiazole-2-thione derivatives have been prepared and assayed for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic human isozymes I and II, and the transmembrane, tumor-associated hCA IX. Against hCA I the investigated thiones, showed inhibition constants in the range of 2.55-222 microM, against hCA II in the range of 2.0-433 microM, and against hCA IX in the range of 1.25-148 microM. Compound 5c, 4-(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)-1-(5-nitro-2-oxoindolin-3-ylidene)semicarbazide showed interesting inhibition of the tumor-associated hCA IX with K(I) value of 1.25 microM, being the first non-sulfonamide type inhibitor of such activity. This result is rather important taking into consideration the known antitumor activity of thiones. In addition, docking of the tested compounds into CA II active site was performed in order to predict the affinity and orientation of these compounds at the isozyme active site. The results showed similar orientation of the target compounds at CA II active site compared with reported sulfonamide type CAIs with the thione group acting as a zinc-binding moiety.     

Design,synthesis and in vitro evaluation against human cancer cells of 5-methyl-5-styryl-2,5-dihydrofuran-2-ones,a new series of goniothalamin analogues

The present work describes the preparation of a novel series of compounds based on the structure of goniothalamin (1), a natural styryl lactone with known cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 17 goniothalamin analogues displaying the 5-methyl-2,5-dihydrofuran-2-one motif were prepared, and their cytotoxicity evaluated. While the analogues bearing methoxy and/or hydroxy groups on the aromatic moiety usually were at least three times less potent than the lead compound (1), ortho and para-trifluoromethyl analogues 10 and 11 exhibited levels of cytotoxicity similar to goniothalamin (1) against most cancer cell lines evaluated. One could suggest that the electronic effect of the trifluoromethyl group activates the inhibitor’s electrophilic site via reduction of the electron density of the α,β-unsaturated ester oxygen atom. These results provide new information on the structure activity relationship of these α,β-unsaturated styryl lactones, thereby further focusing the design of novel candidates.     

Design, new synthesis, and calcilytic activity of substituted 3H-pyrimidin-4-ones

Design, new synthesis, structure-activity relationship studies and calcium receptor antagonist (calcilytic) properties of novel 3H-pyrimidin-4-ones are described.     

Design,synthesis, and antibiofilm activity of 2-arylimino-3-aryl-thiazolidine-4-ones

A series of novel 2-arylimino-3-aryl-thiazolidine-4-ones was designed, synthesized and tested for in vitro antibiofilm activity against Staphylococcus epidermidis. Among them tested, some compounds with carboxylic acid groups showed good antibiofilm activity. The antibiofilm concentration of 1x was 6.25 μM. The structure–activity relationships revealed that incorporation of 2-phenylfuran moiety could greatly enhance antibiofilm activity of thiazolidine-4-one.     

Design, synthesis and in vitro antitumor activity of new trans 2-[2-(heteroaryl)vinyl]-1,3-dimethylimidazolium iodides

The design, the synthesis, and the in vitro antitumor activities of trans 2-[2-(heteroaryl)vinyl]-1,3-dimethylimidazolium iodides versus MCF7 (human mammary carcinoma) and LNCap (prostate carcinoma) cell lines are reported. The design indicates trans 2-[2-[5-(2-chlorophenyl)furan-2-yl]vinyl]-1, 3-dimethylimidazolium iodide 5 and trans 2-[2-[5-(4-bromophenyl)furan-2-yl]vinyl]-1, 3-dimethylimidazolium iodide 6 as highly active compounds in the series. The synthesis of the above new derivatives and in vitro antitumor tests, confirm their significant antiproliferative and cytotoxic activities.     

Synthesis,in silico and in vitro studies of new 1,4-dihydropiridine derivatives for antitumor and P-glycoprotein inhibitory activity

P-glycoprotein (P-gp) is one of the cell membrane pumps which mediate the efflux of molecules such as anticancer drugs to the extracellular matrix of tumor cells. P_gp is a member of the ATP-binding cassette (ABC) transporter family that is implicated in cancer multidrug resistance (MDR). Since MDR is a contributor to cancer chemotherapy failure, modulation of efflux pumps is a viable therapeutic strategy. In this study, new synthetic 1,4 dihydropiridine (DHP) derivatives containing thiophenyl substitution were tested as inhibitors of P-gp. Efflux assay was conducted to evaluate the intracellular accumulation of Rhodamine123 (Rh123) as a pump substrate. MTT assay, cell cycle analysis and in silico methods were also examined. Flow cytometric analysis revealed that synthetic DHP derivatives (15 µM) increased intracellular concentration of the substrate by 2–3 folds compared with verapamil as a standard P-gp inhibitor. MTT assay on EPG85-257P and its drug-resistant EPG85-257RDB cell line revealed antitumor effects (30–45%) for new DHP derivatives at 15 µM following 72 h incubation. However, MTT test on normal cell line showed negligible toxic effects. Finally combination of synthetic derivatives with doxorubicin showed that these compounds decrease IC50 of doxorubicin in resistant cell lines from 9 to 1.5 µM. Sub-G1 peak-related apoptotic cells showed a stronger effect of synthetic compounds at 5 µM compared with verapamil. Molecular dynamic results showed a high binding affinity between DHP derivative and protein at drug binding site. Findings of these biological tests indicated the antitumor activity and P-gp inhibitory effects of new 1,4-DHP derivatives.     

Synthesis of aristolactam analogues and evaluation of their antitumor activity

A series of natural aristolactams and their analogues have been prepared and evaluated for antitumor activity against human cancer cells, including multi-drug resistant cell lines. Naturally occurring aristolactams, such as aristolactam BII (cepharanone B), aristolactam BIII, aristolactam FI (piperolactam A), N-methyl piperolactam A, and sauristolactam showed moderate antitumor activities in selected cell lines. However, several synthetic aristolactam derivatives exhibited potent antitumor activities against a broad array of cancer cell lines with GI₅₀ values in the submicromolar range.     

Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation

A range of amines was reacted with norcantharidin (2) to provide the corresponding norcantharimides (9-43). Treatment of norcantharidin with allylamine afforded the corresponding allyl-norcantharimide (20) which was amenable to epoxidation (mCPBA, 22) and subsequent ring opening (MeOH/H(+); 23) or alternatively, osmylation (OsO(4)/NMO; 24). These simple synthetic modifications of 2 facilitated the development of a novel series of norcantharimides displaying modest to good broad spectrum cytotoxicity against HT29 and SW480 (colorectal carcinoma); MCF-7 (breast adenocarcinoma); A2780 (ovarian carcinoma); H460 (lung carcinoma); A431 (epidermoid carcinoma); DU145 (prostate carcinoma); BE2-C (neuroblastoma); and SJ-G2 (glioblastoma). Analogues possessing a C(10), C(12) or C(14) alkyl chain or a C(12) linked bis-norcantharimide displayed the highest levels of cytotoxicity.     

Preparation of 1,3,5-thiadiazine-2-thione derivatives of chitosan and their potential antioxidant activity in vitro

Three new kinds of 1,3,5-thiadiazine-2-thione derivatives of chitosan with two different molecular weight (SATTCS1, SATTCS2, TITTCS1, TITTCS2, CITTCS1 and CITTCS2) have been prepared. Their structures were characterized by IR spectroscopy. The substitution degree of derivatives calculated by elemental analyses was 0.47, 0.42, 0.41, 0.38, 0.41 and 0.36, respectively. The result shows that substitution degree of derivatives was higher with lower molecular weight. The antioxidant activity was studied using an established system, such as hydroxyl radical scavenging, superoxide radical scavenging and reducing power. Antioxidant activity of the 1,3,5-thiadiazine-2-thione derivatives of chitosan were stronger than that of chitosans and antioxidant activity of low molecular weight derivatives were stronger than that of high molecular weight derivatives. It is a potential antioxidant in vitro.     

Design, synthesis, and antitumor activity of bile acid-polyamine-nucleoside conjugates

A series of bile acid-polyamine amides conjugated with 3'-azido-3'-deoxythymidine (AZT) as potential antitumor prodrugs in the form of phosphoramidates were synthesized in good yields and their antitumor activities were assayed against two human cancer cells in vitro: cervix cancer HeLa cells and renal cancer 7860 cells. The improved antitumor activity probably derived from the enhanced delivery efficiency of AZT due to bile acid-polyamine conjugates.     

Design, synthesis and nootropic activity of new analogues of sunifiram and sapunifiram, two potent cognition-enhancers

A series of amides and sulfonamides, structurally related to DM235 (sunifiram) and MN19 (sapunifiram), derived by ring expansion or contraction, or by inversion of the exocyclic amide function, have been synthesized and tested for cognition-enhancing activity in the mouse passive-avoidance test. Some of the compounds display good antiamnesic and procognitive activity, with higher potency than piracetam, and with a potency similar to the parent compounds.     

Design, synthesis, and anti-inflammatory activity both in vitro and in vivo of new betulinic acid analogues having an enone functionality in ring A

Fifteen new betulinic acid analogues were designed, synthesized, and tested for anti-inflammatory activity. Many of these analogues effectively suppress nitric oxide (NO) production in RAW cells stimulated with interferon-γ. Analogue 10 is highly and orally active in vivo for induction of the anti-inflammatory and cytoprotective enzyme, heme oxygenase-1.     

Design, synthesis and in vitro evaluation of novel bivalent S-adenosylmethionine analogues

In optimal cases, bivalent ligands can bind with exceptionally high affinity to their protein targets. However, designing optimised linkers, that orient the two binding groups perfectly, is challenging, and yet crucial in both fragment-based ligand design and in the discovery of bisubstrate enzyme inhibitors. To further our understanding of linker design, a series of novel bivalent S-adenosylmethionine (SAM) analogues were designed with the aim of interacting with the MetJ dimer in a bivalent sense (1:1 ligand/MetJ dimer). A range of ligands was synthesised and analyzed for ability to promote binding of the Escherichia coli methionine repressor, MetJ, to its operator DNA. Binding of bivalent SAM analogues to the MetJ homodimer in the presence of operator DNA was evaluated by fluorescence anisotropy and the effect of linker length and structure was investigated. The most effective bivalent ligand identified had a flexible linker, and promoted the DNA-protein interaction at 21-times lower concentration than the corresponding monovalent control compound.     

Design, synthesis and activity as acid ceramidase inhibitors of 2-oxooctanoyl and N-oleoylethanolamine analogues

The synthesis of novel N-acylethanolamines and their use as inhibitors of the aCDase is reported here. The compounds are either 2-oxooctanamides or oleamides of sphingosine analogs featuring a 3-hydroxy-4,5-hexadecenyl tail replaced by ether or thioether moieties. It appears that, within the 2-oxooctanamide family, the C3-OH group of the sphingosine molecule is required for inhibition both in vitro and in cultured cells. Furthermore, although the (E)-4 double bond is not essential for inhibitory activity, the (E) configuration is required, since the analogue with a (Z)-4 unsaturation was not inhibitory. None of the oleamides inhibited the aCDase in vitro. Conversely, with the exception of N-oleoylethanolamine and its analogs with S-decyl and S-hexadecyl substituents, all the synthesized oleamides inhibited the aCDase in cultured cells, although with a relatively low potency. We conclude that novel aCDase inhibitors can evolve from N-acylation of sphingoid bases with electron deficient-acyl groups. In contrast, chemical modification of the N-oleoylsphingosine backbone does not seem to offer an appropriate strategy to obtain aCDase inhibitors.     

Design, synthesis, and acetylcholinesterase inhibitory activity of novel coumarin analogues

Three series (series A-C) of coumarin analogues with phenylpiperazine functions as substitution were designed and synthesized for studying their potential for treating Alzheimer's (AD) disease. Their anticholinesterase activities were assayed according to Ellmann's method against freshly prepared acetylcholinesterase (AChE) from Electrophorus electricus using donepezil as the reference compound. Pharmacological study and preliminary structure-activity relationships showed that coumarins with substitution on positions 3 and/or 4 have parallel anti-AchE activities compared with the reference compound.     

Design, synthesis and antitumor activity of 4-aminoquinazoline derivatives targeting VEGFR-2 tyrosine kinase

We report herein the design and synthesis of novel 4-aminoquinazoline derivatives based on the inhibitors of VEGFR-2 tyrosine kinases. The VEGFR-2 inhibitory activities of these newly synthesized compounds were also evaluated and compared with that of ZD6474. We found that most of target compounds had good inhibitory potency. In particular, compounds 1h, 1n and 1o were found to be 6, 2 and 2-fold more potent than the positive control ZD6474. The leading compound 1h also showed an in vivo activity against HepG2 human tumor xenograft model in BALB/c-nu mice.     

Design, synthesis, and cytostatic activity of novel cyclic curcumin analogues

A series of novel cyclic analogues of curcumin were synthesized and analyzed for in vitro cytostatic activity. Condensation of 2-acetylcycloalkanones with a variety of aromatic aldehydes resulted in the formation of 2-arylidene-6-(3-arylacryoyl)-cycloalkanone derivatives. A number of these analogues were found to have significant anticancer activity against representative murine and human cancer cell lines during in vitro bioassays. This corroborated with in vitro cytostatic activity against a panel of 60 cell lines studied at the National Cancer Institute (USA).