Eric De Clercq

Nucleotide Delivery from cycloSaligenyl‐3′‐azido‐3′‐deoxythymidine Monophosphates (cycloSal‐AZTMP)

The application of our cycloSaligenyl- (cycloSal) pronucleotide concept to the approved anti-HIV dideoxynucleoside 3′-azido-3′-deoxythymidine AZT (1) is reported. This pro-nucleotide concept has been designed to deliver the corresponding 3′-azido-3′-deoxythymidine monophosphate AZTMP (2) by selective chemical hydrolysis from the lipophilic precursors cycloSal-AZTMP 4a−h. All derivatives 4a−h were synthesized using differently substituted salicyl alcohols 7a−h as starting materials. In hydrolysis studies, compounds 4 decomposed selectively releasing AZTMP (2) and the salicyl alcohols 7 following the designed tandem reaction. Furthermore, due to the electronic properties introduced by substituents, the half-lives of the triesters 4 could be ajusted over a wide range. Phosphotriesters 4 exhibited considerable biological activity in HIV-1 and HIV-2 infected wild-type human T-lymphocyte (CEM/O) cells, whereas, contrary to our expectations, nearly all activity was lost in HIV-2 infected thymidine-kinase-deficient CEM cells.

Local administration of cidofovir for human papilloma virus associated skin lesions in transplant recipients

Human papilloma virus (HPV)‐associated diseases are increasingly diagnosed in solid organ recipients. Cidofovir (CDV) is a broad‐spectrum antiviral agent with activity against all human herpes viruses and HPV. From 2000–2004, a total of 1303 solid organ transplants (SOT) were performed at our center. Six transplant recipients were treated with topical CDV for HPV‐associated lesions. One cardiac recipient responded to a single injection of CDV into his recurrent anal condylomata. In a renal recipient with recurrent penile condylomata CDV was injected into the lesions four times (2 week interval) until lesions regressed. One renal recipient developed multiple vaginal and anal intradermal neoplasias, which relapsed after laser ablation. The lesions were repeatedly injected with CDV and completely disappeared. Two renal recipients with widespread verrucae vulgares were treated with CDV gel, which resulted in regression of the lesions. One patient developed donor derived verrucae vulgares on both transplanted hands, which responded to CDV gel. Four of the six patients were switched from calcineurin inhibitors (CNIs) to Sirolimus (SIR). CDV was found effective in the treatment of HPV‐associated skin lesions in SOT recipients. It needs to be determined whether switch from CNIs to SIR might have contributed to the beneficial effect of CDV.

The novel phosphoramidate derivatives of NSAID 3-hydroxypropylamides: synthesis, cytostatic and antiviral activity evaluations.

The target phosphoramidates 5a-e were prepared in one step from 3-hydroxypropyl derivatives 3a-e of nonsteroidal anti-inflammatory drugs (fenoprofen, ketoprofen, ibuprofen, indomethacin, diclofenac). The products 3a-e and 5a-e were evaluated for their cytostatic and antiviral activity against malignant tumour cell lines and normal human fibroblasts (WI 38). All phosphoramidate derivatives 5a-e possess significantly greater inhibitory activities than the corresponding 3-hydroxypropyl derivatives 3a-e, whereby compound 5a showed the most potent inhibitory activities against cervical, pancreatic and colon carcinoma cell lines (IC(50)=5-7 microM).

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 IIIB 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.

Novel agents for the therapy of varicella-zoster virus infections

Varicella-zoster virus (VZV), a member of the herpesvirus family, is responsible for both primary (varicella or chickenpox) as well as recurrent (zoster or shingles) infections. Acyclovir has been the mainstay for treating VZV infections in both immunocompetent and immunocompromised patients. Recently, newer anti-VZV drugs, i.e., valaciclovir (the oral prodrug form of acyclovir) and famciclovir (the oral prodrug form of penciclovir) have been developed and have enlarged the therapeutic options to treat VZV infections. Both acyclovir and penciclovir are dependent on the virus-encoded thymidine kinase (TK) for their intracellular activation. Although emergence of drug-resistant strains does not occur in immunocompetent patients, several reports have documented the isolation of drug-resistant VZV strains following long-term acyclovir therapy in immunocompromised patients. Mutations at the level of the TK are responsible for development of resistance to drugs that depend on the viral TK for their phosphorylation (i.e., acyclovir and penciclovir). Foscarnet, a direct inhibitor of the viral DNA polymerase, which does not require activation by the viral TK, is the drug of choice for the treatment of TK-deficient VZV mutants emerging under acyclovir therapy. Recently, emergence of foscarnet-resistant strains has also been reported. Both TK-deficient strains and foscarnet-resistant mutants are sensitive to the acyclic nucleoside phosphonate cidofovir, CDV, HPMPC, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine. This agent does not depend on the virus-encoded TK, but on cellular enzymes for its conversion to the diphosphoryl derivative, which then inhibits the viral DNA polymerase.

New Synthesis and Antitumor Activity of CycloSal- Derivatives of 5-Fluoro-2′-deoxyuridinemonophosphate

Abstract An improved synthesis of 5′-cycloSal-FdUMP 3a-g and 3′,5′-bis-cycloSal-FdUMP 9a-g as potential prodrugs of FdU 1 is described. In hydrolysis studies, phosphotriesters 3 released FdUMP 2 selectively by a tandem reaction. The biological activity of cycloSal-phosphotriesters 3 and 9 was evaluated in different cell lines.

Cyclo-saligenyl-5-fluoro-2′-deoxyuridinemonophosphate (cycloSal-FdUMP) — A New Prodrug Approach for FdUMP

Abstract The synthesis of cycloSal-FdUMP 3a-d as a new prodrug approach for FdU 1 is described. Phosphotriesters 3 release the FdUMP 2 selectively by a controlled, chemically induced tandem reaction in hydrolysis studies. The biological activity (IC50) of cycloSal-phosphotriesters 3 was evaluated in FM3A/O cells and FM3A/TK− cells.

2′-C-ALKOXY AND 2′-C-ARYLOXY DERIVATIVES OF N-(2-PHOSPHONOMETHOXYETHYL)-PURINES AND -PYRIMIDINES: SYNTHESIS AND BIOLOGICAL ACTIVITY

A series of novel, unusual type of acyclic phosphonate-based nucleotide analogues related to well-known antivirals (PMEA and HPMPA) was synthesized using easily available synthon. These compounds, which are distinguished for the presence of phosphonomethyl acetal linkage, form a group of derivatives that contribute to the understanding of structure-activity relationship within the area of acyclic nucleotide analogues.

Cyclo-Saligenyl-3′-Azido-2′,3′-Dideoxy- Thymidinemonophosphate (cycloSal-AZTMP) - A New Pro-Nucleotide Approach1 ?-

Abstract The synthesis of cycloSal-AZTMPs 3a-h as new pro-nucleotides of AZTMP 2 is described. Phosphotriesters 3 selectively release AZTMP 2 by a controlled, chemically induced tandem reaction. CycloSal-AZTMPs 3 exhibited high biological activity in HIV-1/HIV-2 infected CEM/O cells but lost their activity nearly completely in CEM/TK- cells.

POMA analyses as new efficient bioinformatics' platform to predict and optimise bioactivity of synthesized 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues.

A series of 43, 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues (D01-D43) were analysed using Petra, Osiris, Molinspiration and ALOGPS (POMA) to identify pharmacophore, toxicity prediction, lipophilicity and bioactivity. All the compounds were evaluated for anti-HIV activity. 3-(4-Chlorophenyl)-N-(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (D07) was found to be the most active with IC(50)>4.83 μM and CC(50) 4.83 μM. 3-(4-Fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carbothioamide (D41) was found to be the most active compound against bacterial strains with MIC of 4 μg/ml, comparable to the standard drug ciprofloxacin while 3-(4-methoxyphenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (D38) was found to be the most active compound against fungal strains with MIC 2-4 μg/ml, however less active than standard fluconazole. Toxicities prediction by Osiris were well supported and experimentally verified with exception of some compounds. In anticonvulsant screening, 3-(4-fluorophenyl)-N-(4-chlorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (D09) showed maximum activity showing 100% (4/4, 0.25-0.5h) and 75% (3/4, 1.0 h) protection against minimal clonic seizure test without any toxicity.