Michel Camplo

Synthesis and anti-human immunodeficiency virus type 1 activities of new peptido-nucleoside analogues

Summary In order to investigate whether antiproteasic peptides coupled to anti-reverse transcriptase nucleosides can act as inhibitors at the different stages of the HIV life cycle, various peptido-nucleosides were synthesized using methodologies involving (benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) as a coupling reagent between the N 4 -cytosinyl moiety and the peptide carboxy terminus. The anti-HIV-1 activity in MT 4 cells of this new class of compounds and their anti-HIV protease activities were determined. Fourteen peptido-nucleosides have been synthesized and six act against both the HIV-protease and viral replication in vitro . Although the activity of the most potent compounds against HIV was found to be one order of magnitude lower than that of the parent nucleoside drug 2′,3′-dideoxy-3′-thiacytidine, this new class of compound could be of biological interest. Indeed, since the in vitro half-lives ( t 1/2 ) of the hydrolysis of the most potent compounds in human plasma were found to be longer than 2.5 h, these analogues could reach the infected cells in their structural integrity. This observation does not exclude that these compounds may exert their antiviral effects as combined prodrugs through extracellular or intracellular hydrolysis.

Synthesis of new 7-membered α-phenylthio cyclic oxamides: HIV inhibitors

Abstract Based on the concept of bioisosterism, we report the computer design and the synthesis of original 7-membered α-phenylthio cyclic oxamides with potent anti HIV-1 properties.

Synthesis and antiviral activity of N-4′-dihydropyridinyl and dihydroquinolinylcarbonyl-2-hydroxymethyl-5-[cytosin-1′-yl]-1,3-oxathiolane derivatives against human immunodeficiency virus and duck hepatitis B virus

Summary Dihydropyridine and dihydroquinoline derivatives of 2-hydroxymethyl-5-[cytosin-1′-yl]- 1,3-oxathiolane ((±)-3TC) have been prepared. The N--4-nicotinate or the N--4-quinoline-carboxylate amides were obtained by reacting nicotinic or quinolinecarboxylic acids with (±)-3TC in the presence of DCC and HOBT. These derivatives were converted into their corresponding N--methylpyridinium and N--methyl quinolinium salts by treatment with MeI in acetone. Reduction of the latter with Na2SS2OO4 gave dihydropyridine and dihydroquinoline compounds. The N--4-trifluorotoluidinonicotinate derivative was obtained from the coupling of niflumic acid and (±)-3TC using BOP and DIEA. The anti-HIV-1 activities of seven derivatives were determined in MT-4 infected cell cultures. Of these compounds, the IC0 v values ranged from 0.1–100 μM, while the IC0 f for (±)-3TC was 0.1 μM. The anti-HBV activities were determined in infected duck hepatocytes. Anti-HBV activities of the (±)-3TC derivatives were half that of the parent drug (±)-3TC. The lipophilicity (partition coefficients) of these compounds were determined. The dihydroquinoline prodrugs had greater lipophilicity than the dihydropyridine analogues.

Thiophenoxy peptides: A new class of HIV replication inhibitors

Abstract A new series of modified peptides inhibitors of HIV is reported. These peptides utilize the isosteric substitution of a methylene group by a sulfur atom in a phenylalanine residue. Two thiophenoxy peptides 9 and 11 inhibit in vitro HIV-1 replication in MT 4 cells with IC 50 values of 5 and 10 μM respectively.

Synthesis of Tetrazole Oxathiolane Nucleoside Analogues and Their Evaluation as HIV-1 Antiviral Agents

Abstract The synthesis of The synthesis of 2-hydroxymethyl-5-[N2-(5′-carboxamido tetrazolyl)]-1,3-oxathiolane (6a and 6b) and 2-hydroxymethyl-5-[N2-(5′-aminotetrazolyl)]-1,3-oxathiolane (7a and 7b) is described. It involved the preparation of suitable 1,3-oxathiolane precursors via cyclocondensation between benzoyloxyacetaldehyde and 2-mercaptoacetaldehyde di-[2-methoxyethyl] acetal, followed by condensation of adequately substituted tetrazoles using trimethylsilyltriflate or titanium tetrachloride as acid catalysts. In a preliminary in vitro study these new tetrazole oxathiolane nucleoside analogues were found inactive against HIV-1 retrovirus.

Synthesis and comparative anti-HIV activities of new acetylated 2′,3′-dideoxy-3′-thiacytidine analogues

Abstract A series of prodrugs of 2′,3′-dideoxy-3′-thiacytidine have been synthesized in an effort to enhance the uptake of the prodrugs by HIV-1 infected cells and to increase the plasma half-life. The anti-HIV 1 activities of the new analogues and their cytotoxicities were determined in MT 4 cells. In vitro hydrolysis of the various drugs including retinoic acid derivatives, indicated that these agents were relatively stable toward plasma esterases. Most prodrugs with higher partition coefficients than 2′,3′-dideoxy-3′-thiacytidine should diffuse into the cells to a greater extent.

Tri-N-Boc-Tetraazamacrocycle-Nucleoside Conjugates: Synthesis and anti-HIV activities

As far as linear N-Boc-polyamines conjugates elicited remarkable anti-HIV activity, the synthesis and anti-HIV properties of cyclic N-Boc-polyamines conjugates such as tetraazamacrocycle-nucleoside were studied. These new conjugates include an ester linkage between the two moieties. They were synthesized using Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate coupling reagent, in the case of N-alkyl polyazamacrocycle derivatives, or through direct condensation of the acyl chloride derivative with nucleoside in the case of N-acyl polyazamacrocycle compounds. None of the new conjugates presented anti-HIV activity greater than that of the corresponding parent nucleosides.

SYNTHESIS AND ANTI-HIV SCREENING OF SOME HETEROCYCLIC COMPOUNDS

Abstract Pyrimidobenzimidazole derivatives (I and II), pyrimidoanthrnquinonimidazole (III), bis-2-amino-2-thiazoline coupled deuteroporphyrine (IX) derivative (IV), acridone derivative (V) and acridine derivatives (VI-VIII) have been synthesized and characterized by using 1H NMR and HRMS spectral data. All these compounds were screened for anti-HIV-1 activity on MT-4 cells in vitro and were found to be inactive at a concentration below 100 μM.

SYNTHESIS OF NEW THIAZOLIDINONE NUCLEOSIDE ANALOGUES

The synthesis of new thiazolididone nucleoside analogues is described. Among the different proposed synthetic pathways, the condensation of various nucleic bases using TMSOTf and Et3N as coupling r...

Synthesis and Biological Evaluation of a New N4-(N-Formyl Peptide)- 2′,3′-Dideoxy-3′-Thiacytidine as Anti-Hiv Prodrug

Abstract The synthesis of a new analogue of 2′,3′-dideoxy-3′-thiacytidine 9 covalently linked to an N-formyl methionyl leucyl phenylalanine peptide is described. This new prodrug analogue has been tested on the one hand as activator of human polymorphonuclear leukocytes (an EC50 value of 1.8 10−5 M was determined from dose-response curve for superoxide production) and on the other hand as inhibitor of the syncitium formation caused by HIV-1 in MT4-cells (IC50 = 8.0± 0.8 μM). In so far as this new prodrug possesses these two biological properties, it represents a useful “chemical-head” capable of targeting specific receptors located on leukocytes membranes.