Corrigendum to: Phosphonium Salt Displays Cytotoxic Effects Against Human Cancer Cell Lines.

Due to an oversight one of the author's name was published wrong in the article entitled "Phosphonium Salt Displays Cytotoxic Effects Against Human Cancer Cell Lines" in "Anti-Cancer Agents in Medicinal Chemistry, 2015, Vol. 17, No. 13. pp. 1796."The correct names of all authors are given below:Dhanyalayam D, Palma G, Cappello AR, Mariconda A, Sinicropi MS, Giordano F, Del Vecchio V, Ramunno A, Arra C, Longo P, Saturnino C.

Correction: Identification of the key structural elements of a dihydropyrimidinone core driving toward more potent Hsp90 C-terminal inhibitors.

Correction for 'Identification of the key structural elements of a dihydropyrimidinone core driving toward more potent Hsp90 C-terminal inhibitors' by S. Teracciano et al., Chem. Commun., 2016, 52, 12857-12860.

Identification of the key structural elements of a dihydropyrimidinone core driving toward more potent Hsp90 C-terminal inhibitors.

Hsp90 C-terminal modulation represents an attractive strategy for the development of potent and safer antitumor compounds. Continuing our investigation on DHPM type inhibitors here we report a new set of potent C-terminal ligands which allowed us to identify the key structural features crucial for the biological activity.

Protective role of palmitoylethanolamide in contact allergic dermatitis.

BACKGROUND: Palmitoylethanolamide (PEA) is an anti-inflammatory mediator that enhances the activation by anandamide (AEA) of cannabinoid receptors and transient receptor potential vanilloid type-1 (TRPV1) channels, and directly activates peroxisome proliferator-activated receptor-alpha (PPAR-alpha). In mice, 2,4-dinitrofluorobenzene (DNFB)-induced contact allergic dermatitis (CAD) in inflamed ears is partly mediated by the chemokine Monocyte Chemotactic Protein-2 (MCP-2) and accompanied by elevation of AEA levels. No datum is available on PEA regulation and role in CAD. OBJECTIVE: We examined whether PEA is produced during DNFB-induced CAD, and if it has any direct protective action in keratinocytes in vitro. METHODS: Eight- to ten-week-old female C57BL/6J wild-type and CB(1)/CB(2) double knock-out mice were used to measure PEA levels and the expression of TRPV1, PPAR-alpha receptors and enzymes responsible for PEA biosynthesis and degradation. Human keratinocytes (HaCaT) cells were stimulated with polyinosinic polycytidylic acid [poly-(I:C)], and the expression and release of MCP-2 were measured in the presence of PEA and antagonists of its proposed receptors. RESULTS: 2,4-Dinitrofluorobenzene increased ear skin PEA levels and up-regulated TRPV1, PPAR-alpha and a PEA-biosynthesizing enzyme in ear keratinocytes. In HaCaT cells, stimulation with poly-(I:C) elevated the levels of both PEA and AEA, and exogenous PEA (10 microM) inhibited poly-(I:C)-induced expression and release of MCP-2 in a way reversed by antagonism at TRPV1, but not PPAR-alpha. PEA (5-10 mg/kg, intraperitoneal) also inhibited DNFB-induced ear inflammation in mice in vivo, in a way attenuated by TRPV1 antagonism. CONCLUSIONS: We suggest that PEA is an endogenous protective agent against DNFB-induced keratinocyte inflammation and could be considered for therapeutic use against CAD.

Furanocoumarins from the aerial parts of Dorstenia contrajerva.

A new glycosylated furanocoumarin, alpha-L-rhamnopyranosyl-(1-->6)-beta-D-glucopyranosyl-bergaptol (1), has been isolated from Dorstenia contrajerva together with three known furanocoumarins, catechin and epicatechin. Their structures were established using high field 2D NMR techniques.

Biological properties of 5,11-dimethyl-6H-pyrido[3,2-b]carbazoles: a new class of potent antitumour drugs.

Thirteen 5,11-dimethyl-6H-pyrido[3,2-b]carbazoles, structurally related to the antitumour drug ellipticine, were tested for their cytotoxicity against the L1210 murine leukaemia cell line and their antitumour activity against both leukaemias and solid tumours. Most of them showed an interesting antitumour activity against L1210 leukaemia, 4-hydroxy-9-chloro-2,3, 5,11-tetramethyl-6H-pyrido[3,2-b]carbazole displaying a high antitumour activity against L1210 and P388 leukaemias, B16 melanoma and M5076 sarcoma. Despite promising cytotoxic activity, 4-ethoxy-5,11-dimethyl-6H-pyrido-[3,2-b]carbazole had no antitumour activity. The ability of four drugs to induce strand breaks in DNA was studied using the single cell gel electrophoresis assay (comet assay). Most of the molecules induced DNA breaks that were totally or partially repaired after 1 h. The effects of these compounds on the L1210 cell cycle were tested as well as their abilities to induce apoptosis in these cells. Three of them induced a G2/M blockade, without any obvious evidence of apoptosis. The other compound, 4-ethoxy-5,11-dimethyl-6H-pyrido[3,2b]carbazole, did not lead to phase-specific blockade, but was a strong inductor of apoptosis in L1210 cells.

Evaluation of analgesic and anti-inflammatory activity of novel beta-lactam monocyclic compounds.

We have examined the in vivo anti-inflammatory and analgesic activity of a new series of monocyclic beta-lactams (azetidinones), similar to others which have been demonstrated to be inhibitors of human leukocyte elastase (HLE), an enzyme involved in degradation processes of connective tissue. Our new compounds have been administered orally (15 mg/kg) to albino rats 30 min before injecting carrageenin in the plantar aponeurosis. Tested compounds have demonstrated a certain activity and stability to gastric hydrolysis, in particular two of them markedly reduced paw edema formation, even if slightly less effectively than indomethacin (reference compound, 5 mg/kg). To evaluate the analgesic activity we carried out the acetic acid writhing test, pretreating rats orally with our compounds 30 min before injecting the acid solution i.p. The same two molecules which showed the anti-inflammatory activity demonstrated a very light analgesic activity. These results suggest the possibility of carrying out further studies, particularly in vitro, on the mechanism of action of our compounds, mechanism which could be the HLE inhibition.

Amide derivatives with H1-antihistaminic effect.

The synthesis and the structure-activity correlation of a series of N-aminoalkylacetamides as H1-antihistaminic agents have been carried out. The compounds were tested in vitro by measurement of the inhibition of histamine-induced contractions on isolated guinea pig ileum; the results are expressed as pA2.

A new class of pyrrolidin-2-ones: synthesis and pharmacological study. II.

The anticonvulsant activity of a second series of pyrrolidin-2-ones (1-2a, 1-4b, 1-9c) was tested on pentylenetetrazole (PTZ) treated mice. The compounds were obtained by acylation of N-(3'-aminopropyl)-2-pyrrolidinone with the suitable acid chloride.

Synthesis, Crystal Structure and Interaction With DNA of N,N'-(Butane-1,4-Diyl)Bis(Guanidinium) Tetrachloroplatinate (II).

The design, synthesis, crystal structure and interaction with DNA of the N,N'-(butane-1,4-diyl)bis(guanidinium) tetrachloroplatinate(ll) are described. Crystal data: a = 8.152(1), b = 8.889(4), c = 10.700(3) A , alpha = 81.59(3), beta = 87.99(5), gamma = 78.48(6) degrees , V = 752(1) A(3), Z = 2 , space group P-1. The structure was refined to R = 0.039 and Rw = 0.046 from 1853 reflections (I > 3sigma(I)). This compound, named PtC(4)Gua, does not exhibit a center of symmetry and the center linker chain C(2) - C(3) - C(4) - C(5) is in gauche conformation. The cation is bisprotonated with the H(+) attached to the imine group of each terminal guanidinium function. The presence of the platinum moiety reinforces the binding of the butane(bis)guanidinium structure with double stranded DNA as judged from thermal denaturation studies and DNA unwinding experiments.

In vivo inhibition of nitric oxide synthase by bisisothiouronium and bisguanidinium salts.

The ability of two S,S'-(alkane-1,omega-diyl) bisisothiouronium dibromides, three N,N'-(alkane-1, omega-diyl) bis guanidinium dinitrates and N,N'-bis (3-guanidinopropyl)piperazine dinitrate to inhibit constitutive (i.e. endothelial and neuronal forms) and inducible forms of nitric oxide synthases has been evaluated in vivo. These compounds, synthesized by two of us (J. C. L. and C. S.), have been tested in vivo; they were administered simultaneously with an irritant (carrageenan lambda) into the pleural cavity. The amount of nitrites collected 0.5 and 7 hours after this injection can be considered as an indicator of nitric oxide (NO) production. According to previous data, the first harvesting time can be related to activation of constitutive NO synthases and the second to activation of inducible NO synthases. These substances significantly inhibited nitrite production as did 2-methyl-2-thiopseudourea sulphate, previously described as a potent inhibitor of NO synthases and considered as the reference compound. The inhibiting effect varied according to the chemical structure of the compounds. Results were significantly different from controls at 0.5 h only with the S,S'-(octane-1,8-diyl) bisisothiouronium dibromide and the S,S'-(nonane-1,9-diyl) bisisothiouronium dibromide at the highest concentration, N,N'-(heptane-1,7-diyl) bisguanidinium dinitrate and N,N'-bis (3-guanidinopropyl)piperazine dinitrate. At 7 h, all the results were significantly different from controls, with a major effect observed with N,N'-(heptane-1,7-diyl) bisguanidinium dinitrate. The most active substances exerted similar effects to the reference substance.

Sequence-selective binding to DNA of bis(amidinophenoxy)alkanes related to propamidine and pentamidine.

The DNA sequences targeted by a complete homologous series of aromatic diamidines have been determined at single-nucleotide resolution via protection from cutting by the endonucleases DNase I, DNase II and micrococcal nuclease. Propamidine, pentamidine and to a lesser extent hexamidine bind selectively to nucleotide sequences composed of at least four consecutive A-T base pairs. In contrast, the binding to DNA of butamidine, heptamidine, octamidine and nonamidine is poorly sequence-selective. Sequences composed of only three consecutive A-T base pairs do not afford a potential binding site for propamidine or the longer homologues, and none of the drugs tolerate the presence of a G-C base pair within the binding site. Experiments with DNA molecules containing inosine in place of guanosine and 2,6-diaminopurine in place of adenine reveal that the lack of binding of propamidine to GC-containing sites is attributable to an obstructive effect of the exocyclic 2-amino group of guanosine. The present data support the view that the local conformation of the double helix (in particular the width of the minor groove) plays a dominant role in the binding reaction and that the capacity of diamidines to recognize AT-rich sequences selectively varies considerably depending on the length of the alkyl chain. The evidence indicates that binding to AT-tracts in DNA must play a role in the biological activity of these diamidines, but there is no simple correlation between binding and pharmacological efficacy.

Synthesis and pharmacological activities of some 2,3,4,5-tetrahydro[1,5]benzo[f]thiazepines.

In search of new biological active agents in the series of [1,5]benzothiazepines, some 2,3,4,5-tetrahydro-N-(5-morpholinopentanoyl)-[1,5]benzo[f] thiazepines were synthesized and examined in vitro for their calcium antagonist activity compared to the Diltiazem one.

Amoebicidal efficiencies of various diamidines against two strains of Acanthamoeba polyphaga.

The first medical cure of Acanthamoeba keratitis was obtained by use of propamidine isethionate. Since then, it has been the basic drug recommended for use in treatment. Because some Acanthamoeba strains have been reported to be resistant to propamidine and propamidine was found to be only weakly cysticidal, superior homologs such as butamidine, pentamidine, hexamidine, heptamidine, octamidine, and nonamidine were tested for their amoebicidal effects on two Acanthamoeba strains isolated from patients with keratitis. Trophozoicidal and cysticidal efficiencies were found to be increased from propamidine to nonamidine; i.e., when the alkyl chain connecting the two benzene rings in their molecular structures was elongated, in comparison with propamidine, hexamidine and octamidine were the most amoebicidal molecules. As a result of these data, a kinetic study carried out on propamidine, hexamidine, and octamidine demonstrated that the amoebicidal effects resulted from two events: the diffusion of molecules through the plasma membrane or the double wall of trophozoites or cysts, respectively, and the lethal effects of molecules on amoebic protoplasm. The diffusion kinetics were increased when the alkyl chain was elongated, i.e., with an increase in the lipophilic properties of molecules. In contrast, the lethal effect kinetics were found to be unchanged by this elongation, indicating that they originated from the cationic surface-active properties induced by the protonated amidine groups attached to each benzene ring, which themselves remained unchanged from one molecule to the other. These results strongly advocate the immediate replacement of propamidine by hexamidine in the medical treatment of Acanthamoeba keratitis; in France, 0.1% hexamidine eyedrops are available (Desomedine). The results also advocate clinical investigations on the efficiency and toxicity of octamidine, which appears to be the most amoebicidal diamidine in vitro.

Mutagenicity of nitro- and amino-substituted carbazoles in Salmonella typhimurium. I. Monosubstituted derivatives of 9H-carbazole.

Mononitro, monoamino and monoacetamido carbazoles were assayed for mutagenicity in Salmonella typhimurium strains TA1535, TA1538, TA1537, TA1977, TA98 and TA100, with and without the addition of S9 from phenobarbital-induced rat liver. The role of bacterial metabolism of the nitro group was also studied using the additional strains TA98NR and TA98/1,8DNP6. None of the compounds was active in TA1535, while only 2-nitrocarbazole and 3-nitrocarbazole presented a weak mutagenicity towards its pKM101 derivative, TA100. All four nitrocarbazole isomers were mutagenic for TA1538 and TA98, their activities decreasing in the order: 2-nitrocarbazole approximately 3-nitrocarbazole > 1-nitrocarbazole > 4-nitrocarbazole. Direct-acting mutagenicities for TA1537 were lower than for TA1538, but varied in the same order. Nitro reduction was an important step of metabolic activation of nitrocarbazoles, as indicated by the dramatic reduction of activity with TA98NR, as compared to TA98. Results obtained with TA98/1,8DNP6 showed that O-acetyltransferase was only partly required for the expression of mutagenic potency of these compounds. 2-Aminocarbazole was a weak direct-acting mutagen for TA1538 and TA98. Its activity was strongly increased in the presence of S9 mix, while 3-aminocarbazole became active in these conditions. The acetamido derivatives were consistently less mutagenic than their parent amines. These results show that nitrocarbazoles and aminocarbazoles behave as reactive frameshift mutagens, acting mainly through the formation of esterified hydroxylamines. The very low activity of 4-nitrocarbazole might be related to an orientation of the nitro group perpendicular to the aromatic ring.

Research on heterocyclic compounds. XXX. Synthesis and pharmacological activity of 2-methylimidazo[1,2-b]pyridazine-3-carboxylic acids.

A group of ethyl 2-methylimidazo[1,2-b]pyridazine-3-carboxylates were prepared by reaction in anhydrous ethanol of some substituted 3-amino-pyridazines with ethyl 2-chloroacetoacetate. The corresponding carboxylic acids were obtained via alkaline or acid hydrolysis and then tested both in vivo to evaluate their antiinflammatory, analgesic and ulcerogenic actions and in vitro for their ability to inhibit the prostaglandin biosynthesis. The pharmacological results are discussed in terms of both structure-activity relationships and mechanism of action.

Research on heterocyclic compounds. XXVII. Synthesis and antiinflammatory activity of 2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acids.

A group of ethyl esters of 2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acids 3 were obtained by reaction in anhydrous ethanol of some substituted 3-aminopyridazines 1 with ethyl 2-benzoyl-2-bromoacetate 2. The acids 4 obtained via alkaline hydrolysis were tested in vivo for their antiinflammatory, analgesic and ulcerogenic actions and in vitro for their ability to inhibit the prostaglandin biosynthesis. Almost all of the new compounds showed high analgesic activity, whereas the activities exhibited in the other tests were sharply lower. These results are discussed in terms of mechanism of action.

Research on heterocyclic compounds. XXIV. Antiinflammatory activity of some imidazo[1,2-c]pyrimidine derivatives.

A group of four acidic imidazo[1,2-c]pyrimidine derivatives were subjected to a series of tests in vivo in order to assess their pharmacological activity. Antiinflammatory activity was studied by means of the carrageenin-induced paw edema and pleurisy in rats. Hot plate test and writhing induced by acetic acid in mice were employed to evaluate analgesic activity, whereas the yeast-induced hyperthermia in rats was used to study antipyretic activity. The irritative and ulcerogenic action on the rat gastric mucosa was examined at higher doses. The inhibitory activity on the platelet malondialdehyde production was studied in order to obtain information about the mechanism of action of test compounds.