Christiane Huel

Diphenyl quinolines and isoquinolines: synthesis and primary biological evaluation.

The synthesis of a series of 35 substituted 3,4-diphenyl quinolines and isoquinolines is described. The majority of these molecules differ from all other triphenylethylene based antiestrogens by a different spatial location of the aminoalkyl side chain. The binding affinity of the most representative molecules (8, 9, 19, 20, 21, 23 and 25), including analogues 8 and 21 without the side chain, for the estrogen receptor alpha (ER) was determined. The ability of these molecules to induce the progesterone receptor was also studied. Antiproliferative activity was evaluated on MCF-7 human breast cancer cells, while intrinsic cytotoxic/cytostatic properties resulting from interaction with other targets than ER were assayed on L1210 murine leukemia cells. Introduction of an aminoalkylamino side chain at carbon 2 confers strong cytotoxic properties to diphenylquinolines 9 and 10 as well as pure antiestrogenic activities. However, cytotoxicity is so high with respect to antiestrogenicity that the latter was clearly observable only in one case (9b). The structure of compound 9b was determined by X-ray crystallography. Molecular modeling of its docking within the hormone-binding domain of the receptor was subsequently undertaken. According to our results, the design of molecules with the side chain bound to the ethylene part of the triphenyl ethylene skeleton might generate compounds of potential pharmacological interest.

A convenient way to dibenzo[c,h]-1,5-naphthyridines (11-aza-benzo[c] phenanthridines)

Abstract Whereas thermal cyclisation of variously substituted 2,3-diarylacrylazides easily provided a new way to 3-aryl-isoquinolones, nitration of these compounds mainly led to corresponding 3-aryl-4-nitro-isoquinolones. After reduction into 4-amino-3-aryl-isoquinolones, amidification and subsequent cyclization gave the yet unknown title compounds.

Methyl Orthocarboxylates as Methylating Agents of Heterocycles

Methylation reactions occurring between trimethyl orthocarboxylates or N,N-dimethylcarboxamide dimethyl acetals and various hydroxylated heterocycles, involving a lactam-lactim tautomeric equilibrium, were investigated as an alternative to classic methylation methods. The corresponding O-methylated or N-methylated compounds were isolated in a number of instances and the reaction’s regioselectivity was shown to sometimes follow and sometimes differ from the corresponding outcome using standard methylation methods. In the course of this work, previously unreported effects were noticed. In one case the use of toluene as a reaction solvent led to much more N-methylated material. In other instances, the influence of the reagent’s steric bulk and/or stability (orthoformate vs. orthoacetate or N,N-dimethylformamide dimethyl acetal vs. its acetamide homologue) was also noticed. An unwanted formylation reaction could sometimes be avoided and, less often, an increase of O-methylated material was observed. The previously unreported 1-dimethoxymethylpyridin-2(1H)-one was characterized and its acid-catalyzed rearrangement into, mostly, 1-methylpyridin-2(1H)-one was studied. The new techniques described here (methanol trapping with 4 A molecular sieves and Lewis acid-catalyzed reaction) greatly increase the potential of trimethyl orthocarboxylates. These reagents can be considered as possible alternatives to the dimethyl formamide-producing N,N-dimethylformamide dimethyl acetal and may sometimes be attractive options compared to the usual carcinogenic and salt-producing methylating agents. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis of 3-aryl-4-acetyl-1H-pyrazolo [3,4-b]-pyridines and 3-aryl-4-acetyl-1H-pyrazolo [4,3-c] pyridines

Acetyl-2-chloro-3-lithiopyridine ethylene glycol ketal and 2-acetyl-4-chloro-3-lithiopyridine ethylene glytcol ketal were reacted with aromatic aldehydes and oxidation of the resulting alcohols provided the corresponding 3-aroylpyridines. These intermediateds were transformed by hydrazine hydrate to 4-acetyl-3-aryl-1H-pyrazolo [3,4-b]- and -[4,3-c] pyridine ethylene glycol ketals, which afforded the title compounds, respectively, by acid hydrolysis

Synthesis and Anti-HIV Evaluation of 7-Deaza Analogues of Carbovir

Abstract Three analogues of Carbovir 1 have been synthesized and evaluated for antiviral activity in vitro. Anti-HIV-1 and anti-HIV-2 activities have been observed with 7-deaza analogues 3 and 5 of 1. Compound 5 was about ten times more potent than 3 against HIV-1 and HIV-2 on different cell lines.

Synthesis of 2-oxa-4-azabicyclo[3.2.1]-octane and -octene systems via X-ray-analyzed trans-3-dibenzamido-cyclopentene-1-oxide

Abstract 3,4- trans -Epoxidation of (cyclopent-3-en-l-yl)dibenzamide gave, in 82% yield, the 1,5-epoxide, the structure of which was confirmed by X-ray crystallographic analysis. Epoxide ring opening by trimethylsilyl cyanide, under the catalysis of diethylaluminum chloride, did not lead to the expected trans -β-trimethylsilyl-oxynitrile as a potential precursor of carbocyclic 2-deoxy- d - erythro -pentofuranosylamine, but to 4-benzamido-3-cyano-3-phenyl-7-trimethylsilyloxy-2-oxa-4-azabicyclo[3.2.1]octane, which resulted from the participation of the benzoyl group in the epoxide ring cleavage.

On the methylation of 3-cyano-6-hydroxypyridine-2(1H)-ones

In order to prepare new heterocyclic derivatives as building block for compounds with potential biological activities, we were led to study the O-methylation of 3-cyano-6-hydroxypyridine-2(1H)-ones such as 1. This enabled us to develop a new two steps method to prepare the corresponding 2,6-dimethoxy derivative 5 in 80 % yield. It consisted first in heating 1 in trimethylorthoformate, with or without an acidic catalyst, which gave a mixture of the two mono-methoxy isomers, then a classical methylation of the second hydroxy moiety led almost exclusively to 5. In this paper we present this “methylation” method and various unexpected results recorded when we attempted to extend it to related derivatives or to other heterocycle containing lactim-lactam functions. An intramolecular transetherification mechanism requiring the simultaneous transfer of a hydrogen and a methyl is suggested.

SYNTHESIS OF CHLORAMPHENICOL AND MANDELONITRILE GALACTOSE-CONTAINING PRODRUGS

The synthesis of O 1-β-d-galactopyranosylchloramphenicol and O 1-β-d-galactopyranosylmandelonitrile as prodrugs potentially substrates of β-galactosidase, are reported. Preparation of O 1-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl) chloramphenicol from unprotected chloramphenicol was successful using β-d-galactopyranose pentaacetate and boron trifluoride diethyl etherate in acetonitrile. However, the β-galactosylated diastereoisomers of racemic mandelonitrile had to be made via O 1-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)mandelamide in dichloromethane prior to dehydration to obtain the nitrile moiety. Indeed, galactosylation trials starting directly from mandelonitrile in acetonitrile led to the O 1-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)mandelonitrile diastereoisomers. From a methodological point of view, this work extends the use of the galactosylation method to new hydroxyl bearing compounds. It also points out that the solvent used (acetonitrile or dichloromethane) and the purity of boron trifluoride diethyl etherate can be crucial factors in the use of this method as an eventual alternative to heavy metal-based Lewis acids usually employed in glycosylation reactions.

New cyclobutyl analogs of nucleosides. Part 2. Synthesis and antiviral evaluation of 2-amino-7-[3,3-bis (hydroxymethyl)cyclobut-1-yl]-3H,7H-pyrrolo-[2,3-d]pyrimidin-4-one and of cyclobutyl analogs of the pyrimidine nucleosides

Abstract The synthesis and antiviral evaluation of a series of 3,3-dihydroxymethyl cyclobutane nucleoside analogs related to the natural anti-HIV nucleoside, oxetanocin A are reported. The different purine and pyrimidine nucleoside analogs described in this paper have been obtained from 1-amino-3,3-dibenzyloxymethylcyclobutane. The compounds were tested against HSV-1, HCMV and HIV-1 in cell cultures, but none of them exhibited activity against these viruses. These results suggest the crucial role of the position of both hydroxymethyl groups in oxetanocin A and oxetanocin G for antiviral activity.

Both-faces hindered porphyrins. Part 4. Synthesis of functionalized basket-handle porphyrins designed for a strict intramolecular axial ligation in superstructured complexes

The concept of basket-handle porphyries, in a cross-trans configuration, is applied to the design of new compounds which possess a chemical group attached to the central carbon of one bridging chain in order to mimic the axial co-ordination of the active site of hemoproteins. The key intermediates used in these syntheses are prepared from 5,1 0,1 5,20-tetraphenylporphyrin the two phenyl groups in opposing positions of which are bridged by a ketonic chain, whilst the two other phenyl groups carry a polymethylene chain, (8b) and (24), or a pyridyl one, (33) and (41), via ether or amide linkages. These compounds are clearly reduced to alcohol derivatives which may be further derivatived under mild conditions to give functionalized porphyries having pendant 0, N, and S donor chemical groups as potential axial ligands. Additional diketonic porphyries (8c) and (40) have been obtained during the preceding synthesis to allow the preparation of symmetrical disubstituted compounds. The characterization of these new superstructured porphyries was established by 1H n.m.r. spectroscopy as well as the relative inner or outer position of the substituted chemical groups.