María José Camarasa

Anti-angiogenic activity of a novel multi-substrate analogue inhibitor of thymidine phosphorylase

7‐Deazaxanthine (7‐DX) was recently identified as the first purine derivative with pronounced inhibitory activity against Escherichia coli thymidine phosphorylase (TP) and angiogenesis. In order to ‘freeze’ the enzyme in an open, inactive conformation, a novel multi‐substrate analogue inhibitor of TP, containing an alkyl phosphonate moiety covalently linked to 7‐DX, was synthesized. The prototype compound TP65 (9‐(8‐phosphonooctyl)‐7‐deazaxanthine) (at 250 μM) completely inhibited TP‐induced formation of microvascular sprouts from endothelial cell aggregates in a three‐dimensional fibrin gel. In the chick chorioallantoic membrane assay, TP caused a dose‐dependent stimulation of angiogenesis, which was completely inhibited by 250 nmol TP65. This dose proved to be non‐toxic for the developing chick embryo. TP65 thus emerges as a potent and specific inhibitor of TP and TP‐induced angiogenesis, which opens new perspectives for multi‐substrate analogue inhibitors of TP as potential anti‐cancer agents and as inhibitors of angiogenesis and of diseases with enhanced expression of TP.

Hiv-1 Specific Reverse Transcriptase Inhibitors: why are Tsao-Nucleosides so Unique?

1. INTRODUCTION AIDS will still be one of the most important challenges for the Scientific Community in the approaching new century. Since the identification, in 1983-84,1,2 of human immunodeficiency virus (HIV) as the etiological agent of AIDS, significant progress has been made in the treatment of HIV-infected patients. This has been in part due to the discovery and clinical use of an increasing number of anti-HIV drugs. However, while highly active antiretroviral therapy (HAART)3 approaches have reduced the morbidity and mortality, the intertwined problems of drug induced viral resistance, poor compliance with complex regimens and therapy failure continue. Therefore, there remains a pressing need for the development of new antiviral agents that can be used not only as first line therapeutic candidates, but also in the antiretroviral-experienced patient population.

TSAO Derivatives: Highly Specific Inhibitors of Human Immunodeficiency Virus Type-1 (HIV-1) Replication

Abstract TSAO derivatives represent a unique class of nucleosides that are specifically targeted at HIV-1 RT. This overview is focussed on the chemical synthesis, the conformational studies, the antiviral and metabolic properties of TSAO derivatives, as well as their mechanism of antiviral action and the molecular basis of the rapid selection of resistant HIV-1 strains that emerge in cell culture in the presence of TSAO derivatives.

SYNTHESIS AND ANTI-HIV-1 ACTIVITY OF 4- AND 5-SUBSTITUTED 1,2,3-TRIAZOLE-TSAO DERIVATIVES

Abstract Several 4- or 5-monosubstituted and 4,5-disubstituted 1,2,3-triazole analogues of the anti-HIV-1 lead compound [1-[2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]thymine]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) (TSAO-T) have been prepared and evaluated for their inhibitory effect against HIV-1-induced cytopathicity.

Antivascular and antitumor properties of the tubulin-binding chalcone TUB091.

We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3’’-amino-4’’-methoxyphenyl)-1-(5’-methoxy-3’,4’-methylendioxyphenyl)-2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-to-straight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs.

Synthesis of 3′-C-ethynylnucleosides of thymine

Abstract Reaction of 1-[2,5-di- O -(t-butyldimethylsilyl)-β- D - erythro -pentofuranos-3-ulosyl]thymine with HCCMgBr gives a (25:1) mixture of 3′- C -ethynyl nucleosides of thymine having β- D - xylo and β- D - ribo configuration. Reaction of 1-(2′-deoxy-5′- O -trityl-β- D -glycero-pentofuran-3-ulosyl)thymine with HCCMgBr gives the corresponding 3′- C -ethynyl-β- D - threo -thymidine. The absolute configurations of the newly formed chiral centers at C-3′ have been demonstrated by chemical means.

Microwave-assisted synthesis of C-8 aryl and heteroaryl inosines and determination of their inhibitory activities against Plasmodium falciparum purine nucleoside phosphorylase

8-Arylinosines have been scarcely studied for therapeutic purposes, probably due to difficulties in their synthesis. The recently described direct arylation reaction at position 8 of purine nucleosides has been employed to synthesize a series of 8-aryl and 8-pyridylinosines. These compounds have been studied for hydrolytic stability and subjected to biological evaluation. Three compounds have shown a pronounced specific inhibition of Plasmodium falciparum-encoded purine nucleoside phosphorylase, an important target for antimalarial chemotherapy.

Mild generation of alkylidenecarbenes from α-mesyloxynitriles of sugars. Application to the synthesis of branched-chain sugars

Treatment of O-mesylcyanohydrins of furanos-3-ulose with sodium azide affords vinylazidoderivaties; the intermediary of an alkylidenecarbene is proposed, and reactions to trap such an intermediate are described.

Nucleosides: Potential Drugs for AIDS Therapy

Recent methods for the synthesis of nucleoside derivatives which have been tested for anti-HIV activity, or which, because of their structure, may be good candidates for testing are described. The nucleoside derivatives considered in this review are 3′-azido-2′,3′-dideoxynucleosides, 2′,3′-dideoxy- β′-fluoronucleosides, 2′,3′-dideoxy-3′-C-substituted nucleosides, 2′,3′-dideoxy-β-d-glycero-pent-2- enofuranosyl nucleosides, 2′,3′-dideoxynucleosides and carbocyclic, acyclic and C-nucleosides. Structure-activity relationships are also considered.

Synthesis of 2-Amino-3-C-(Carboxymethyl)-2,3-Dideoxy-Allopyranose Derivatives

Abstract The Wittig reaction of methyl 2-acetamido-4,6-O-benzylidene-2-deoxy-α-d-ribo-hexopyranosid-3-ulose witethoxycarbonylmethylenetriphenylphosphorane afforded the corresponding 3-C-(E)-ethoxycarbonyle-thyiene-3-deoxy glycoside 3. Catalytic hydrogenation of 3 (Pd/C) gave stereoselectively, after removal of benzylidene and ethyl ester protecting groups, methyl 2-acetamido-3-C-carboxymethyl-2,3-dideoxy-α-D-allo-hexopyranoside (11).