Synthesis and anti-HIV activity of 2′-deoxy-2′-fluoro-4′-C-ethynyl nucleoside analogs

Based on the favorable antiviral profiles of 4′-substituted nucleosides, novel 1-(2′-deoxy-2′-fluoro-4′-C-ethynyl-β-d-arabinofuranosyl)-uracil (1a), -thymine (1b), and -cytosine (2) analogs were synthesized. Compounds 1b and 2 exhibited potent anti-HIV-1 activity with IC₅₀ values of 86 and 1.34 nM, respectively, without significant cytotoxicity. Compound 2 was 35-fold more potent than AZT against wild-type virus, and also retained nanomolar antiviral activity against resistant strains, NL4-3 (K101E) and RTMDR. Thus, 2 merits further development as a novel NRTI drug.     

A New Synthesis of 2-chloro-2′-deoxyadenosine (Cladribine), CdA)

A new efficient route for the synthesis of 2-chloro-2′;-deoxyadenosine (Cladribine), CdA) has been developed. The key step of this method was selective deprotection of the acetyl group at the 2′ position; the 3′, 5′ acetyl groups were not affected. This can be accomplished efficiently with hydroxylamine hydrochloride and sodium acetate in pyridine. The 2′ hydroxyl group was removed by the Barton-McCombie reaction. Using this strategy, CdA was prepared in five steps and 31.0% yields.     

Ester Derivatives of Nucleoside Inhibitors of Reverse Transcriptase: 2. Molecular Systems for the Combined Therapy with 3′-Azido-3′-Deoxythymidine and 2′,3′-Didehydro-3′-Deoxythymidine

The methods of synthesis of conjugates of anti-HIV nucleosides with various compounds, such as protease inhibitors, peptides, polysaccharides, and bicyclames are considered; they are designated for the combined therapy of HIV.     

Synthesis and Biological Activities of Sugar-Modified 2-(p-n-Butylanilino)-2′-deoxyadenosine Analogues

Abstract

Several sugar-modified 2-(p-n-butylanilino)-2′-deoxyadenosine analogues, including arabino and 2′(R)-azido-2′-deoxy analogues and their 5′-triphosphates were synthesized. These nucleosides thus obtained exhibited moderate cytotoxicity against P-388 leukemic cells in culture (IC₅₀ = 13–24 μ). In contrast to above results, the 5′-triphosphates have been shown to exert strong and selective inhibitory effects on mammalian DNA polymerase α (Ki= 0.02–0.04 μ).     

Ester Derivatives of Nucleoside Inhibitors of Reverse Transcriptase: 1. Molecular Transport Systems for 3′-Azido-3′-Deoxythymidine and 2′,3′-Didehydro-3′-Deoxythymidine

The methods of synthesis of the derivatives of nucleoside analogues esterified with various aliphatic, aromatic, and heteroaromatic acids and the construction from them of molecular transport systems that involve lipids, carbohydrates, peptides, and amino acids are discussed. The characteristics of the biological activity of a number of such systems are described.__________Translated from Bioorganicheskaya Khimiya, Vol. 31, No. 4, 2005, pp. 339–356.Original Russian Text Copyright © 2005 by Berezovskaya, Chudinov.     

Determination Of 2-Chloro-2′-deoxyadenosine (Antileukemic Agent) and Related Compounds by Electrochemical Method

Abstract

Electrochemical method for determination of 2-chloro-2′-deoxyadenosine and related compounds modified in exocyclic 6-NH₂ group is described. Electrochemical detection of investigated compounds, based on the electrooxidation process of the adenine moiety, has been performed in aqueous solutions, in the pH range 2–9, on a glassy carbon electrode     

Synthesis of 1-O-(2′,4′-Dichlorophenoxyacetyl)-d-glucopyranose

1-O-Glucosyl esters of 2,4-dichlorophenoxyacetic acid (2,4-D) were easily prepared from 4,6-O-benzylideneglucose. The configuration of 1-O-ester linkage was affected by pH at the end of the reaction, that is, β-type was a major product at a neutral or acidic condition and α-type at an alkaline condition. Both of the anomers showed the same biological activities as sodium salt of 2,4-D.     

MicroRNA-7 Inhibits Multiple Oncogenic Pathways to Suppress HER2Δ16 Mediated Breast Tumorigenesis and Reverse Trastuzumab Resistance

The oncogenic isoform of HER2, HER2Δ16, is expressed with HER2 in nearly 50% of HER2 positive breast tumors where HER2Δ16 drives metastasis and resistance to multiple therapeutic interventions including tamoxifen and trastuzumab. In recent years microRNAs have been shown to influence multiple aspects of tumorigenesis and tumor cell response to therapy. Accordingly, the HER2Δ16 oncogene alters microRNA expression to promote endocrine resistance. With the goal of identifying microRNA suppressors of HER2Δ16 oncogenic activity we investigated the contribution of altered microRNA expression to HER2Δ16 mediated tumorigenesis and trastuzumab resistance. Using a gene array strategy comparing microRNA expression profiles of MCF-7 to MCF-7/HER2Δ16 cells, we found that expression of HER2Δ16 significantly altered expression of 16 microRNAs by 2-fold or more including a 4.8 fold suppression of the miR-7 tumor suppressor. Reestablished expression of miR-7 in the MCF-7/HER2Δ16 cell line caused a G1 cell cycle arrest and reduced both colony formation and cell migration activity to levels of parental MCF-7 cells. Suppression of miR-7 in the MCF-7 cell line resulted in enhanced colony formation activity but not cell migration, indicating that miR-7 suppression is sufficient to drive tumor cell proliferation but not migration. MiR-7 inhibited MCF-7/HER2Δ16 cell migration through a mechanism involving suppression of the miR-7 target gene EGFR. In contrast, miR-7 inhibition of MCF-7/HER2Δ16 cell proliferation involved a pathway where miR-7 expression resulted in the inactivation of Src kinase independent of suppressed EGFR expression. Also independent of EGFR suppression, reestablished miR-7 expression sensitized refractory MCF-7/HER2Δ16 cells to trastuzumab. Our results demonstrate that reestablished miR-7 expression abolishes HER2Δ16 induced cell proliferation and migration while sensitizing HER2Δ16 expressing cells to trastuzumab therapy. We propose that miR-7 regulated pathways, including EGFR and Src kinase, represent targets for the therapeutic intervention of refractory and metastatic HER2Δ16 driven breast cancer.     

Structural Determinants of HIV-1 Reverse Transcriptase Stereoselectivity Towards (β)-L-Deoxy- and Dideoxy-Pyrimidine Nucleoside Triphosphates: Molecular Basis for the Combination of L-Dideoxynucleoside Analogs with Non-nucleoside Inhibitors in Anti HIV Chemotherapy

Abstract

We have compared the HIV-1¹ RT mutants containing the single substitutions L100I, K103N, V106A, V179D, Y181I and Y188L, known to confere NNI-resistance in treated patients, to HIV-1 RT wt for their sensitivity towards inhibition by D- and L-deoxy- and dideoxy-nucleoside tiphosphates. The results showed a differential effect of the substitutions on the affinity for both D- and L-enantiomers of deoxy- and dideoxy-nucleoside triphosphates and provide a rationale for the utilization of L-dideoxynucleoside analogs with NNI in combination chemotherapy.