Synthesis and evaluation of antileukemic activity of 5-thienyl- or 5-(2-furyl)-2,3-dihydro-6,7-bis(hydroxymethyl)-1H-pyrrolizine bis(alkylcarbamates) and derivatives.

Treatment of N-(2-furoyl)proline or N-thenoylprolines and N-(2-thenoyl)thiazolidine-4-carboxylic acid with acetic anhydride and dimethyl acetylenedicarboxylate gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate and derivatives of dimethyl 5-(2-thienyl)pyrrolo[1,2-c]thiazole. Reduction of 2 with lithium aluminum hydride gave the diols 3a, 3b, 3c and 3d. These diols yielded the corresponding diacetates 4 by treatment with acetic anhydride. The bis(methylcarbamates) 5a, 5b, 5c, and 5d and bis(isopropylcarbamates) 6b and 6c are obtained with the appropriate isocyanates. The 1-substituted pyrrolizines were synthesized, the 1-acetoxy compounds 7b and 7c further transformed into 1-hydroxy and 1-oxo analogues. The action of hydrochloric acid on 1-acetoxy derivatives gave 3H-pyrrolizines. Evaluation of antileukemic activity was investigated on the leukemia L1210 in vivo, on several bis(alkylcarbamates). The compounds 5c and 5d show good antileukemic activity comparable with the mitomycin.

Novel and selective partial agonists of 5-HT3 receptors. 2. Synthesis and biological evaluation of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines.

In continuation of our previous work on piperazinopyrrolothienopyrazine derivatives, three series of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines were prepared and evaluated as 5-HT3 receptor ligands. The chemical modifications performed within these new series led to structure-activity relationships regarding both high affinity and selectivity for the 5-HT3 receptors that are in agreement with those established previously for the pyrrolothienopyrazine series. The best compound (8a) obtained in these new series is in the picomolar range of affinity for 5-HT3 receptors with a selectivity higher than 10(6). Four of the high-affinity 5-HT3 ligands (8a, 15a,b, and 16d) were selected in both the pyridopyrrolopyrazine and the pyrroloquinoxaline series and were characterized in vitro and in vivo as agonists or partial agonists. Compound 8a was also evaluated in the light/dark test where it showed potential anxiolytic-like activity at very low doses per os.

Novel selective and partial agonists of 5-HT3 receptors. Part 1. Synthesis and biological evaluation of piperazinopyrrolothienopyrazines.

A series of piperazinopyrrolo[1,2-a]thieno[3,2-e]- and -[2,3-e]pyrazine derivatives were prepared and evaluated in order to determine the necessary requirements for high affinity on the 5-HT3 receptors and high selectivity versus other 5-HT receptor subtypes. Various substitutions on the piperazine and the thiophene ring of the pyrrolothienopyrazine moieties were systematically explored as well as replacement of the piperazine by other cyclic amines. The best compounds are in the nanomolar range of affinity of 5-HT3 receptors with high to very high selectivity (up to 10,000 for 14b). These high-affinity compounds have in common a benzyl- or allylpiperazine substituent with no substitutions on the thiophene ring. Five of these compounds (1a, 4b, 13a,b, and 14b) have been evaluated on the Von Bezold-Jarisch reflex and were characterized as partial agonists. One of them, 13a, has shown in vivo at very low dose a potent anxiolytic-like activity in the light/dark test.

Highly potent and selective ligands for a new class H3 of histamine receptor.

The third histamine receptor was first indentified on brain neurons and seems to be present in other cells such as lung mast cells. Hence the novel and potent H3-receptor agonist (R) alpha-methylhistamine might find therapeutic applications in allergic diseases.

Effect of cetiedil analogs on acetylcholine and choline fluxes in synaptosomes and vesicles.

Cetiedil is a potent blocker of acetylcholine and choline fluxes. Several analogs of this compound have been synthesized and their effect on acetylcholine (ACh) and choline fluxes in synaptosomes and on ACh uptake in synaptic vesicles have been studied. The effects of these analogs were compared to those of other drugs acting on cholinergic functions. All these compounds were also studied in relation to the ACh translocating properties of the mediatophore, a protein recently purified from cholinergic nerve membranes and probably involved in the final step of release. We thus obtained a pattern of drug action for the three functions under study. The patterns of drug action on ACh release from synaptosomes or proteoliposomes were similar and clearly different from those for either synaptosomal choline transport or vesicular ACh uptake. In addition, the main outlines of the structure-function relationship for each of the functions studied, are described for cetiedil analogs.

Synthesis of cone, partial-cone, and 1,3-alternate 25, 27-Bis

The preparation of 25,27-bis[1-(2-ethyl)hexyl]- and 25, 27-bis[1-(2-tert-butoxy)ethyl]calix[4]arene-crown-6 combining one polyether crown-6 and one alkylchain O-attached on each side of a calix[4]arene in the cone, partial-cone, and 1,3-alternate conformations are reported. The control over 25, 27-bisalkylcalix[4]arene-crown-6 conformation via varying specific reaction conditions was studied. The series of calix[4]arenes have been prepared by two routes, which differ in the order in which the alkyl or polyether groups were introduced. Moreover, methods have been developed to selectively prepare the cone and partial-cone conformers by using an appropriate base in the alkylation reactions. The conformations of these new derivatives have been probed by (1)H NMR analysis and X-ray crystallography. The (1)H and (13)C NMR spectra of 25,27-bis[1-(2-ethyl)hexyl]calix[4]arene-crown-6, 1, 3-alternate 1, cone 2, and partial-cone 3 are also discussed.

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.

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.

An environmentally sustainable decision model for urban solid waste management.

The aim of this work is to present the structure and the application of a decision support system (DSS) designed to help decision makers of a municipality in the development of incineration, disposal, treatment and recycling integrated programs. Specifically, within a MSW management system, several treatment plants and facilities can generally be found: separators, plants for production of refuse derived fuel (RDF), incinerators with energy recovery, plants for treatment of organic material, and sanitary landfills. The main goal of the DSS is to plan the MSW management, defining the refuse flows that have to be sent to recycling or to different treatment or disposal plants, and suggesting the optimal number, the kinds, and the localization of the plants that have to be active. The DSS is based on a decision model that requires the solution of a constrained non-linear optimization problem, where some decision variables are binary and other ones are continuous. The objective function takes into account all possible economic costs, whereas constraints arise from technical, normative, and environmental issues. Specifically, pollution and impacts, induced by the overall solid waste management system, are considered through the formalization of constraints on incineration emissions and on negative effects produced by disposal or other particular treatments.

[Anti-AIDS thienopyrimidine nucleosides]. / Nucléosides thiénopyrimidiniques à visée anti-sida.

In response to the AIDS epidemic, the discovery of antiviral agents has been focused on the synthesis of nucleoside analogues. The basis moiety of these pyrimidine nucleosides were thieno and thiano[3,2-d]pyrimidine-2,4-dione possibly substituted on 7 position by methyl or aryl groups, 6,7-dihydrothieno[3,2-d]pyrimidin-4-one, bicyclic heterocycles including an uracil moiety. The first part of organic chemistry work has provided cyclic and acyclic N-nucleosides after adaptation of Vorbrüggen and Niedballa method. The carbohydrate fraction of these nucleosides included either a cyclic sugar yielding uridine, ARA U and IDU analogues or an hydroxylated chain that allowed access to aciclovir, ganciclovir and EBPU analogues. The second part has been devoted to functional arrangements beta-D-ribonucleoside respectively on carbohydrate and aglycon moieties carrying into reduction (synthesis of an unsaturated dideoxynucleoside, a d4T analogue) and amination reactions (cytidine analogue). Several compounds were tested against HIV1 in CEM cl 13 cell cultures, but none of them exhibited significant activity against this virus.

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.

[Potential interest in powerful and specific ligands for the histamine H3 receptor]. / Intérêt potentiel de ligands puissants et spécifiques du récepteur H3 de l'histamine.

In contrast to cerebral histamine H1 and H2-receptors, histamine H3-receptors are presynaptically located on histamine-synthesizing nerve terminals (autoreceptors) and control the synthesis and release of the amine in cerebral neurons. Two imidazole derivatives were designed to interact at H3-receptors: (R) alpha-methylhistamine (alpha-MeHA), a chiral agonist, and thioperamide, a competitive antagonist derived from imidazolyl piperidine, both display high selectivity and potency at nanomolar concentrations in vitro. (R) alpha-MeHA, being about 15 times as potent as histamine itself, constitutes, when tritiated, a suitable probe for the radioassay of H3-receptors. Outside the brain, H3-receptor sites could be detected in the lung. The availability of new ligands made it possible to assess in vivo the physiological role of central and peripheral H3-receptors. The agonist and the antagonist modified in opposite directions histamine synthesis in the lung as in the brain, confirming the presence of H3-receptors in this peripheral organ. A large part of lung histamine being present within mast-cells, it is likely that these cells are endowed with H3-receptors controlling the amine synthesis and, possibly, release. Therefore, the novel agents may be of great practical interest in the field of allergy and inflammation.

Comparative molecular field analysis of CCK-A antagonists using field-fit as an alignment technique. A convenient guide to design new CCK-A ligands.

Comparative molecular field analysis (CoMFA) has been used as a three-dimensional quantitative structure-activity relationship (QSAR) method to correlate the affinities of several antagonists towards CCK-A receptors with their steric and electrostatic fields. In this publication, we describe, for the first time, a field-fit operation as an alignment technique. These results could serve as a guide for the design of new non-peptide antagonists.

Mass spectral study of chlorofluorocarbons (CFCs) and potential alternatives (HCFCs and HFCs).

Owing to high ozone depletion potential of the chlorofluorocarbons (CFCs), the production of such substances has been regulated worldwide by the Montreal Protocol in 1987. There is an urgent need to find other suitable products to replace them and hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs) are considered to be the most probable candidates as CFC alternatives. The HCFCs and HFCs are more susceptible to decomposition during use than CFCs because they contain hydrogen. Toxicological data on these alternative fluorocarbons are being developed. A systematic investigation of these compounds has been undertaken to establish the fragmentation patterns. Electron impact mass spectra are reported for HCFCs and HFCs. Fragmentation mechanisms are presented and discussed on the basis of variable energy (11 to 30 eV) spectra. At low ionization energy, it is possible to describe an order of fragmentation for each compound. This may lead to the possibility of classifying them according to characteristic behaviors.

Applicability of CoMFA in ecotoxicology: a critical study on chlorophenols.

Comparative molecular field analysis (CoMFA) is used to relate ecotoxicological data with steric and electrostatic fields of chemicals forming an intentionally selected homogeneous set, the chlorophenols, for which reliable data are abundant in literature. Among these data, those concerning 16 different biological systems were selected, leading to predictive CoMFA QSAR in 14 of the cases. This is attested by cross-validation and bootstrapping, which also authorize the prediction of the chlorophenols toxicity values, when they are missing. The quality of obtained CoMFA models and the applicability of the method are discussed. The results are very promising, and they encourage further investigation into CoMFA in ecotoxicology.

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 pharmacologic study of pyridazino[4,5-b]carbazoles]. / Synthèse et etude pharmacologique de pyridazino[4,5-b]carbazoles.

Cyclization reaction of hydrazine with carbazole-2,3-methyl dicarboxylates gave 1,4-dioxo-1,2,3,4-tetrahydropyridazino[4,5-b]carbazoles. Chlorodehydroxylation provided 1,4-dichloropyridazino[4,5-b]carbazoles and nucleophilic substitution gave 1,4-dialkoxy pyridazino[4,5-b]carbazoles. These compounds were tested for cytotoxic activity against L1210 leukemia in mice.