Publications

Increased Absorption of the Antiviral Ester Prodrug Tenofovir Disoproxil in Rat Ileum by Inhibiting Its Intestinal Metabolism

Synthesis and antiviral activity of acyclic analogues of 1,5-anhydrohexitol nucleosides using Mitsunobu reaction

Molecular strategies to inhibit the replication of RNA viruses

ChemInform Abstract: Synthesis and Biological Evaluation of Some Cyclic Phosphoramidate Nucleoside Derivatives.

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.

ChemInform Abstract: Synthesis and anti‐HIV Activity of New Modified 1,2,3‐Triazole Acyclonucleosides.

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.

Sulfated polymers inhibit the interaction of human cytomegalovirus with cell surface heparan sulfate

Clinical significance of chemokine receptor antagonists

<b>Introduction</b>: Chemokine receptors are important therapeutic targets for the treatment of many human diseases. This study will provide an overview of approved chemokine receptor antagonists and promising candidates in advanced clinical trials.<b>Areas covered</b>: We will describe clinical aspects of chemokine receptor antagonists regarding their clinical efficacy, mechanisms of action, and re-purposed applications.<b>Expert opinion</b>: Three chemokine antagonists have been approved: (i) plerixafor is a small-molecule CXCR4 antagonist that mobilizes hematopoietic stem cells; (ii) maraviroc is a small-molecule CCR5 antagonist for anti-HIV treatment; and (iii) mogamulizumab is a monoclonal-antibody CCR4 antagonist for the treatment of mycosis fungoides or Sézary syndrome. Moreover, phase 3 trials are ongoing to evaluate many potent candidates, including CCR5 antagonists (e.g. leronlimab), dual CCR2/CCR5 antagonists (e.g. cenicriviroc), and CXCR4 antagonists (e.g. balixafortide, mavorixafor, motixafortide). The success of chemokine receptor antagonists depends on the selective blockage of disease-relevant chemokine receptors which are indispensable for disease progression. Although clinical translation has been slow, antagonists targeting chemokine receptors with multifaced functions offer the potential to treat a broad spectrum of human diseases.

Synthesis and Antiviral Activity of 1,3-Disubstituted Uracils against HIV-1 and HCMV

The development of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) is an efficient strategy for finding new therapeutic agents against human immunodeficiency virus (HIV). A large number of 6-substituted uracil derivatives have been prepared in order to explore new NNRTIs. However, there are few approaches to anti-HIV agents from 1,3-disubstituted uracil derivatives. Therefore, we tried to prepare several 1,3-disubstituted uracils, which were easily obtainable from uracil by preparation under alkali and Mitsunobu conditions, and examined their antiviral activity against HIV-1 and human cytomegalovirus (HCMV). We found that 1-benzyl-3-(3,5-dimethylbenzyl)uracil and 1-cyanomethyl-3-(3,5-dimethylbenzyl)-4-thiouracil showed powerful inhibition against HCMV and HIV-1, respectively.

Synthesis and Antiviral Activity of Carbocyclic Nucleosides Incorporating a Modified Cyclopentane Ring. Part 3: Adenosine and Uridine Analogues

Six new carbocyclic nucleosides were prepared by mounting a purine (compounds 4-6), 8-azapurine (7 and 8) or uridine (9) base on the amino group of (1S,3R)-3-amino-2,2,3-trimethylcyclopentylmethanol (10). At subtoxic concentrations, compounds 5-9 showed at best marginal antiviral activity.

Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors

An Interactive CAPP Kernel Based on a Blackboard System Architecture

This paper describes the ideas and developments that lead to a new Computer Aided Process Planning (CAPP) approach : a blackboard-style, interactive CAPP system, in which the human process planner is assisted by expert modules, each capable of performing a process planning task. At all times, the human operator has full control over all planning activities. An important reasoning mechanism, that is inevitably linked with the interactive CAPP kernel, is opportunistic process planning. The implementation of this mechanism in an automatic feature based CAPP system will also be elaborated in this paper.

Synthesis, characterization, antitumor, and cytotoxic activity of mononuclear Ru(II) complexes

In the search for antitumor active metal complexes several ruthenium complexes have been reported to be promising. A series of mononuclear Ru(II) complexes, [Ru(T)2(S)]2+, where T = 2,2′-bipyridine/1,10-phenanthroline and S = CH3-bitsz, Cl-bitsz, Br-bitsz, tmtsz, dmtsz, have been prepared and characterized by UV-Vis, IR, 1H-NMR, FAB-mass spectroscopy, and elemental analysis. The complexes were subjected to in vivo anticancer activity against a transplantable murine tumor cell line Ehrlich's ascitic carcinoma (EAC) and in vitro cytotoxic activity against human cancer cell line Molt 4/C8, CEM, and murine tumor cell line L1210. Ruthenium complexes showed promising biological activity especially in decreasing tumor volume and viable ascitic cell counts. Treatment with these complexes prolonged the life span of EAC-tumor-bearing mice by 10–48%. In vitro evaluation of these ruthenium complexes revealed cytotoxic activity from 0.21 to 24 µmol L−1 against Molt 4/C8, 0.16–19 µmol L−1 against CEM, and 0.75–32 µmol L−1 against L1210 cell proliferation, depending on the nature of the compound.

A novel inhibitor of the CRM1-mediated Rev export

An Efficient Synthesis of a Hydroxyethylamine (HEA) Isostere and Its α‐Aminophosphonate and Phosphoramidate Derivatives as Potential Anti‐HIV Agents

HIV protease is a promising drug target for AIDS therapy, and several potent HIV-1 protease inhibitors have been reported to date. Although existing inhibitors exhibit high selectivity, they have also been associated with severe side effects and the possible emergence of therapeutic resistance. As HIV protease cleaves the peptide bond via a tetrahedral intermediate, various transition-state models such as hydroxyethylamine (HEA) have been designed. We therefore pursued an efficient synthesis of an HEA isostere; this was performed with a novel one-pot reduction-transimination-reduction reaction sequence as a key step. α-Aminophosphonate and phosphoramidate derivatives of the HEA isostere were designed and synthesized, and all of the synthesized derivatives were assayed for their anti-HIV activities against wild-type and mutant HIV strains. Phosphoramidate derivative 15 a was found to be the most active of all synthesized compounds against the III(B) and RES056 strains. As phosphonates are known to exhibit physiological stability, good cell permeability, and other promising pharmacokinetic characteristics, our newly synthesized compounds have the potential as alternatives to existing therapeutics and diagnostics.

Combination of the multidrug resistance mutation Q151M/L and the AZT resistance mutation T215Y/F in the same HIV-1 reverse transcriptase is compatible with enzymatic activity

Novel (E)-5-(2-iodovinyl)-2'-deoxyuridine derivatives as potential cytostatic agents against herpes simplex virus thymidine kinase gene transfected tumors.

(E)-5-(2-Iodovinyl)-2'-deoxyuridine (IVDU), its 2'-fluoro-substituted derivatives IVFRU (with fluorine in the ribo configuration), IVFAU (with fluorine in the ara configuration), and the corresponding 3'-chemical delivery system (CDS), or 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)- substituted derivatives IVDU-CDS, IVFRU-CDS and IVFAU-CDS were evaluated for their cytostatic activity against wild-type (FM3A/O), thymidine kinase (TK)-deficient (FM3A/TK-), and herpes simplex virus type 1 (HSV-1) or HSV-2 thymidine kinase (tk) gene-transfected murine mammary carcinoma FM3A cells (FM3A TK-/HSV-1 TK+ and FM3A TK-/HSV-2 TK+). The test compounds proved highly inhibitory to the proliferation of HSVtk gene-transfected FM3A cells. Their cytostatic activity was within the 0.002 to 0.80 microM range, a compound concentration that is 1000- to 10,000-fold lower than that required to inhibit proliferation of wild-type FM3A/O cells. The target for the cytostatic activity of the test compounds is the cellular thymidylate synthase. In contrast to the parent IVDU compound, IVFRU and IVFAU and their CDS-substituted derivatives proved resistant to phosphorolytic cleavage by human and bacterial thymidine phosphorylase and should be considered as promising candidate compounds for further evaluation for combined gene/chemotherapy of HSVtk gene-transfected tumor cells in animal models.

Pyranodipyrimidines (PDPs): a new class of HIV integrase inhibitors that block viral replication in cell culture

Productive Infection of Primary Macrophages with Human Herpesvirus 7

Here we demonstrate replication of human herpesvirus 7 (HHV-7), a T-lymphotropic virus, in macrophages. Productive replication was lost after 2 weeks, but HHV-7 DNA was detected up to 1 month after infection. Thus, macrophages become infected by HHV-7 and might play an important role as a viral reservoir, as has been demonstrated for human immunodeficiency virus type 1.