Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
Add more filters










Database
Language
Publication year range
1.
J Org Chem ; 71(8): 3082-5, 2006 Apr 14.
Article in English | MEDLINE | ID: mdl-16599603

ABSTRACT

In this paper, we report a simple route to accede to a new family of C-10 fluorinated derivatives of artemisinin 7. We demonstrated that nucleophilic substitution of the allylic bromide 6 with alcohols can occur at carbon 10 (compounds 7) under solvolytic conditions (S(N)'/S(N) ratio, 87:13). Furthermore, using the particular properties of hexafluoroisopropanol (HFIP), we are able to increase the selectivity of the substitution. Primary alcohols are completely selective for allylic substitution. With amines as nucleophiles, selectivity of substitution is dependent on their nucleophilicity, but attack at carbon 16 was always favored. However, the S(N)'/S(N) ratio could be slightly increased by adding HFIP, which is able to modulate their nucleophilicity through hydrogen bonding. In preliminary in vitro assessments, these new compounds, 7, exhibited a satisfying activity against malaria.


Subject(s)
Artemisinins/chemistry , Fluorine/chemistry , Sesquiterpenes/chemistry , Amines/chemistry , Artemisinins/chemical synthesis , Molecular Structure , Sesquiterpenes/chemical synthesis
2.
J Org Chem ; 70(2): 699-702, 2005 Jan 21.
Article in English | MEDLINE | ID: mdl-15651823

ABSTRACT

The synthesis of the title compound is described through original and tailored synthetic protocols. The addition of vinylmagnesium bromide to CF(3)-N-aryl and N-alkyl aldimines was efficient and did not require an activating N-substituent. The resultant CF3-allylamines were converted in an efficient and completely stereoselective route to syn CF3-epoxides 3 via formation of bromhydrins 8. The same sequence performed from the aldimine substituted with the methyl ether of the (R)-phenylglycinol provided the homochiral (R,R)-amino epoxide (de >98%). This study has allowed access to the novel racemic and homochiral trifluoromethyl beta-amino epoxides, analogues of key precursors of various HIV protease inhibitors.


Subject(s)
Amines/chemical synthesis , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Epoxy Compounds/chemical synthesis , Prodrugs/chemical synthesis , Amines/chemistry , Amines/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Epoxy Compounds/chemistry , Epoxy Compounds/pharmacology , Molecular Structure , Prodrugs/chemistry , Prodrugs/pharmacology , Stereoisomerism
3.
J Org Chem ; 69(13): 4336-50, 2004 Jun 25.
Article in English | MEDLINE | ID: mdl-15202887

ABSTRACT

In connection with a total synthesis of cephalotaxine (1a), we have examined the addition of various nucleophilic reagents to [ABC] subunits 2 and 7 possessing a pyrrolobenzazepine core. In fact, this reaction implicates invariably the carbonyl group of 2. Regarding the reaction of 7 with nucleophiles, the most striking aspect is the complete lack of reactivity of the enaminonitrile moiety. For instance, the condensation of 7 with methylmagnesium bromide involves exclusively the cleavage of the dioxole ring, yielding regioisomers 9 and 10. With the aim of understanding the unexpected reactivity of 2 and 7 toward nucleophiles, crystallographic studies of 2 and 7 and an experimental electron density determination of 7 were carried out. The marked reactivity of the carbonyl group of 2 was interpreted by invoking the weakness of the amide resonance, due to a pronounced delocalization of the N(9) lone pair over the enaminonitrile moiety. The electron density study of 7 reveals this electron delocalization along the enaminonitrile fragment, highlighted and quantified through the bond geometries, topological indicators, and atomic charges, a phenomenon that is responsible for the failure of the addition of nucleophilic species.


Subject(s)
Benzazepines/chemistry , Nitriles/chemistry , Crystallography , Electrons , Harringtonines/chemical synthesis , Homoharringtonine , Models, Molecular , Molecular Structure , Nitriles/chemical synthesis
4.
J Med Chem ; 47(6): 1423-33, 2004 Mar 11.
Article in English | MEDLINE | ID: mdl-14998331

ABSTRACT

New fluoroartemisinin derivatives containing polar or water-soluble functionalities at C-16 (11a-j, 12a-g) were synthesized using the key intermediate 16-bromo-10-trifluoromethyl anhydrodihydroartemisinin 10. The substitution reaction from 10 was more selective than that from the nonfluorinated parent bromide; the allylic bromide 10 underwent no allylic rearrangement and provided only nucleophilic substitution products in high yields with N-, O-, and C-nucleophiles. Among them, amines 11a-c appeared to be highly in vivo efficient antimalarials on mice infected with Plasmodium berghei, more than the reference sodium artesunate 1d. In particular, the most effective piperazinoethanol derivative 11b cured all mice after oral treatment at a dose lower than 10 mg/kg. Further pharmacokinetic studies showed that the bioavailability in rats following oral administration was 25 times greater for 11b than for artemether 1b.


Subject(s)
Antimalarials/chemical synthesis , Artemisinins/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Administration, Oral , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Artemisinins/chemistry , Artemisinins/pharmacology , Biological Availability , Drug Resistance , Drug Stability , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Hydrolysis , Malaria/drug therapy , Mice , Plasmodium berghei , Plasmodium falciparum/drug effects , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship
5.
J Org Chem ; 68(25): 9763-6, 2003 Dec 12.
Article in English | MEDLINE | ID: mdl-14656104

ABSTRACT

To prepare 10-trifluoromethyl analogues of important antimalarials such as artemether and artesunate, the substitution reaction of the 10-trifluoromethyl hemiketal 6 and bromide 4 derived from artemisinin was investigated. While 6 appeared to be unreactive under various conditions, bromide 4 could easily undergo substitution with methanol under electrophilic assistance or noncatalyzed conditions. Optimization of the reaction revealed the role of CH(2)Cl(2) as solvent to avoid the competitive elimination process and the crucial influence of hexafluoro-2-propanol (HFIP) in increasing the rate and the stereoselectivity of the substitution reaction (de >98%). The efficiency of this reaction was exemplified with various alcohols and carboxylates (yield up to 89%).


Subject(s)
Antimalarials/chemical synthesis , Artemisinins/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Propanols/chemistry , Sesquiterpenes/chemical synthesis , Alcohols/chemistry , Artemether , Artesunate , Bromine/chemistry , Carboxylic Acids/chemistry , Methyl Chloride/chemistry
6.
Chembiochem ; 4(8): 754-61, 2003 Aug 04.
Article in English | MEDLINE | ID: mdl-12898627

ABSTRACT

The goal of our study was to potentiate the effects of the ((R,R)-trans-1,2-diaminocyclohexane)-platinum(II) fragment [(DACH)Pt], known for its cytotoxic properties, either with tamoxifen (Tam), the most widely used antiestrogen in the treatment of hormone-dependent breast cancers, or with its active metabolite hydroxytamoxifen (hydroxy-Tam). We coupled Tam or hydroxy-Tam derivatives bearing a malonato group at the para position of the beta aromatic ring with the (DACH)Pt fragment. The malonato-Tam and malonato-hydroxy-Tam compounds were prepared through McMurry coupling of the appropriate ketones. The presence of the malonate group resulted in a pronounced stereospecificity in the reaction, since malonato-Tam was obtained only as the Z isomer, while malonato-hydroxy-Tam was obtained as an 80/20 E/Z mixture. Attribution of the isomeric structures was achieved by 2D NMR spectroscopy. The platinum complexes (DACH)Pt-malonato-Tam and (DACH)Pt-malonato-hydroxy-Tam were then prepared by coupling the barium salts derived from the malonato-Tam and malonato-hydroxy-Tam with the nitrate derived from (DACH)PtCl(2). Study of the biochemical properties of these two platinum complexes showed that, while the hydroxy-Tam complex is satisfactorily recognized by the estrogen receptor (relative binding affinity, RBA=6.4 %), the Tam complex is less well recognized (RBA=0.5 %). The effects of these complexes on two hormone-dependent breast cancer cell lines (MCF7 and MVLN) were studied in vitro. Both complexes showed an antiproliferative effect on MCF7 cells, and an antiestrogenic effect on MVLN cells. The observed effects appear to be essentially antihormonal, since incorporation of the (DACH)Pt fragment into the tamoxifen skeleton did not cause an increase in the cytotoxicity of the complexes.


Subject(s)
Antineoplastic Agents, Hormonal/chemical synthesis , Antineoplastic Agents, Hormonal/pharmacology , Organoplatinum Compounds/chemical synthesis , Tamoxifen/chemical synthesis , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Division/drug effects , Female , Humans , Organoplatinum Compounds/pharmacology , Receptors, Estrogen/metabolism , Tamoxifen/pharmacology , Tumor Cells, Cultured
7.
J Org Chem ; 67(4): 1253-60, 2002 Feb 22.
Article in English | MEDLINE | ID: mdl-11846670

ABSTRACT

The preparation of the 10-trifluoromethyl hydroartemisinin, followed by dehydration, afforded the trifluoromethyl analogue 2 of anhydrodihydroartemisinin 1. The reactivity of these two glycals of artemisinin were compared in epoxidation and halogenation reactions. Iodination of glycal 1 in water and the further rearrangement of the produced iodo hemiacetal provided the new D-ring-contracted aldehyde 8alpha, where the methyl at C-9 is beta. Epoxidation of 10-trifluoromethyl anhydrodihydroartemisinin 2 stereoselectively provided the beta-epoxy ether 11 in high yield. When treated with hexafluoro-2-propanol or trifluoroethanol, 11 readily underwent a rearrangement yielding to the D-ring-contracted trifluoromethyl ketone 9alpha with retention of configuration at C-9.


Subject(s)
Artemisinins , Sesquiterpenes/chemistry , Sesquiterpenes/chemical synthesis , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Catalysis , Hydrolysis , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Structure , Stereoisomerism , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...