Publications

Potential drugs for the treatment of AIDS

From our investigations the following compounds have emerged as particularly potent and selective inhibitors of HIV replication: sulphated polysaccharides (i.e. heparin, dextran sulphate, pentosan polysulphate), dideoxynucleoside analogues such as the 3'-azido-and 3'-fluoro-substituted 2',3'-dideoxyribosides of both purines (i.e. guanine, 2,6-diaminopurine) and pyrimidines (i.e. uracil, thymine), and the 9-(2-phosphonylmethoxyethyl) derivatives of adenine, 2-monoaminopurine and 2,6-diaminopurine. All these compounds yield great promise for the treatment of retrovirus infections in humans. Whereas the sulphated polysaccharides interfere with the virus adsorption process, the nucleoside analogues (following intracellular phosphorylation to their 5'-triphosphate) appear to be targeted at the reverse transcriptase.

Differential inhibitory effects of Evans blue on various DNA polymerases.

Evans Blue, an anionic dye which has been found to inhibit the replication of human immunodeficiency virus, proved also inhibitory to the DNA polymerases alpha and beta. The mode of inhibition was competitive with respect to the template X primer, and noncompetitive with respect to the deoxynucleoside triphosphate substrates. The inhibitory effect of Evans Blue on DNA polymerases is discussed in relation to that of suramin.

5′,5′‐di‐<i>O</i>‐nucleosyl‐<i>O</i>′‐benzylphosphotriesters as potential prodrugs of 3′‐azido‐2′,3′‐dideoxythymidine‐5′‐monophosphate

Abstract The synthesis of 5′,5′‐ O ‐di‐(3′‐azido‐2′,3′‐dideoxythymidinyl)‐ O ′‐benzylphosphotriesters 1 as potential prodrugs of nucleoside monophosphates is described. The concept is applied to the antiretroviral nucleoside analog 3′‐azido‐2′,3′‐deoxythymidine (AZT) 4. All derivatives 1 were synthesized by reaction of the tetra‐ n ‐butylammonium salt of di‐AZT‐phosphate 2b with different benzyl bromides or ‐chlorides 9. Compound 2b was obtained by a combination of phosphoamidite/H‐phosphonate chemistry, subsequent oxidation to 2a , and cation exchange. The partition coefficients of 1 in an 1‐octanol/water mixture show that all compounds exhibit a much higher lipophilicity than the parent nucleoside AZT ( 4 ). It was also shown, that 1 decomposes spontaneously under mild aqueous basic conditions (phosphate buffer (pH 7.5) and RPMI culture medium containing heat‐deactivated fetal calf serum) releasing selectively the di‐AZT phosphate anion 2. The half‐lives of 1 could be adjusted within a wide range by changing the ring substituents of the benzyl group. Additionally, the mechanism of hydrolysis varies if the substituent is changed from a donor to an acceptor one. The described phosphotriesters 1 exhibit considerable antiviral activity in HIV‐1‐ and HIV‐2‐infected CEM/O cells, whereas no activity was detected in the HIV‐2‐infected thymidine kinase‐deficient CEM cell line. On the other hand, we could not detect any cytotoxicity of the described phosphotriesters. Consequently, compounds 1 should act as prodrugs or depot forms at least of antiviral nucleoside analogs.

CCDC 144157: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Trisubstituted benzimidazoles as NNRTIs: synthesis and anti-HIV evaluation

Synthesis and Biological Activities of C (5)‐N‐Spin‐Labeled Uridines and Related Derivatives

Abstract Direct introduction of a N‐atom in one step at C (5) of 5‐hydroxyuridine (4a) or 5‐hydroxy‐2′‐deoxyuridine (4b) by certain primary amines led to the synthesis of two novel C(5)‐N‐spin‐labeled nucleoside analogs and to several C(5)‐N‐aryl adducts. Substitution by 4‐amino‐2,2,6,6‐tetramethylpiperidinooxyl (3) at C(5) of 4a or 4b led to the spin‐labeled nucleosides 5‐[(1‐oxyl‐2,2,6,6‐tetramethyl‐4‐piperidinyl)amino]uridine and ‐2′‐deoxyuridine ( 2a and 2b , respectively). The analogous C(5)‐substituted aniline adducts 5‐anilino uridine (5a) and 5‐anilino‐2′‐deoxyuridine (5b) and the p ‐toluidine adducts 5‐( p ‐toluidino)uridine (6a) and 5‐( p ‐toluidino)‐2‐deoxyuridine (6b) were also prepared. In addition, results of the antiviral and antimetabolic activity of some of these analogs are reported.

Does Ortho-Substitution Enhance Cytotoxic Potencies in a Series of 3,5-Bis(benzylidene)-4-piperidones?

<b>Background:</b> A series of 3,5-benzylidene-4-piperidones, <b>1a</b>-<b>n</b>, were prepared to evaluate the hypothesis that the placement of different groups in the ortho-location of the aryl rings led to compounds with greater cytotoxic potencies than structural analogs. <b>Methods:</b> The bioevaluation of <b>1a</b>-<b>n</b> was undertaken using human Molt/4C8 and CEM cells as well as murine L1210 cells. Correlations were sought between the interplanar angles θ_A and θ_B and the cytotoxic potencies. A QSAR analysis was also undertaken. In order to evaluate whether these compounds demonstrated greater toxicity to neoplasms than non-malignant cells, <b>1a</b>-<b>n</b> were evaluated against HSC-2, HSC-3, HSC-4 and HL60 neoplasms as well as non-malignant HGF, HPC and HPLF cells. <b>Results:</b> A positive correlation was noted between the interplanar angle θ_A of one of the aryl rings and the adjacent olefinic linkage with IC₅₀ values in the Molt4/C8 screens. The QSAR analysis revealed a positive correlation between the Hansch pi (π) value of the aryl substituents and the IC₅₀ values of the compounds towards the Molt4/C8 and CEM cells. The dienones in series <b>1</b> demonstrated higher tumor-selective toxicity towards HSC-2, HSC-3, HSC-4 and HL-60 neoplasms than HGF, HPC and HPLF cells. <b>Conclusions:</b> The bioevaluations revealed some support for greater cytotoxic potencies to be displayed by compounds having ortho-substituents.

CCDC 144155: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

ChemInform Abstract: Synthesis, Conformation Analysis and Biological Evaluation of 2‐(2,3‐ Dideoxy‐β‐D‐ribofuranosyl)pyridine‐4‐carboxamide.

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Lenacapavir: A capsid inhibitor for HIV-1 treatment and prevention

ChemInform Abstract: Synthesis and Antiviral Evaluation of N‐β‐D‐Ribosides of Ergot Alkaloids.

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis, Anti-Human Immunodeficiency Virus Activity and Esterase Lability of Some Novel Carboxylic Ester-Modified Phosphoramidate Derivatives of Stavudine (d4T)

We report the design, synthesis and antiviral evaluation of a series of lipophilic, masked phosphoramidate derivatives of the anti-human immunodeficiency virus (HIV) nucleoside analogue d4T, designed to act as membrane-soluble prodrug forms for the free nucleotide. In particular, we report a series of 12 novel compounds with systematic variation in the structure of the carboxylate ester function. In order to rationalize the changes in antiviral action with variation of this moiety we applied our recently developed 31P NMR-based assay for carboxyesterase lability to this series. However, no clear positive correlation emerged, indicating that, at least within this series, factors other than simple esterase lability may be the major determinants of antiviral potency.

Resistance profile of human immunodeficiency virus to mannose-binding proteins

Bicyclic nucleoside inhibitors of Varicella-Zoster Virus (VZV): the effect of a terminal halogen substitution in the side-chain

Selective inhibition of human immunodeficiency virus (HIV) by 3′-Azido-2′,3′-dideoxyguanosine invitro

Synthesis and antiviral evaluation of benzimidazoles, quinoxalines and indoles from dehydroabietic acid

Inhibition of the in vitro growth of Plasmodium falciparum by acyclic nucleoside phosphonates

ChemInform Abstract: Novel Carbocyclic Nucleosides Containing a Cyclobutyl Ring: Adenosine Analogues.

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.