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Telomerase Inhibitor (telomerase + inhibitor)

Distribution by Scientific Domains

Medical Sciences	50%
Chemistry	50%

Selected Abstracts

An Efficient Formal Synthesis of the Human Telomerase Inhibitor (±)-,-Rubromycin,

ANGEWANDTE CHEMIE, Issue 43 2009
Dominea
Balanceakt: Das Gleichgewicht der elektronischen Faktoren im Naphthazarin- und Isocumarin-Fragment erleichtert die säurevermittelte Cyclisierung zum dicht funktionalisierten Spiroketal (siehe Bild; EOM=Ethoxymethyl) in einer formalen Synthese von (±)-,-Rubromycin. Eine Sequenz aus regioselektiver Allyloxylierung und Claisen-Umlagerung macht das hoch oxygenierte Naphthazarin-Fragment ausgehend von 2-Azido-1,4-naphthochinon zugänglich. [source]

Oligonucleotide N3,,P5, Phosphoramidates and Thio -Phoshoramidates as Potential Therapeutic Agents

CHEMISTRY & BIODIVERSITY, Issue 3 2010
Sergei
Abstract Nucleic acids analogues, i.e., oligonucleotide N3,,P5, phosphoramidates and N3,,P5, thio -phosphoramidates, containing 3,-amino-3,-deoxy nucleosides with various 2,-substituents were synthesized and extensively studied. These compounds resist nuclease hydrolysis and form stable duplexes with complementary native phosphodiester DNA and, particularly, RNA strands. An increase in duplexes' melting temperature, ,Tm, relative to their phosphodiester counterparts, reaches 2.2,4.0° per modified nucleoside. 2,-OH- (RNA-like), 2,- O -Me-, and 2,- ribo -F-nucleoside substitutions result in the highest degree of duplex stabilization. Moreover, under close to physiological salt and pH conditions, the 2,-deoxy- and 2,-fluoro-phosphoramidate compounds form extremely stable triple-stranded complexes with either single- or double-stranded phosphodiester DNA oligonucleotides. Melting temperature, Tm, of these triplexes exceeds Tm values for the isosequential phosphodiester counterparts by up to 35°. 2,-Deoxy-N3,,P5, phosphoramidates adopt RNA-like C3,- endo or N -type nucleoside sugar-ring conformations and hence can be used as stable RNA mimetics. Duplexes formed by 2,-deoxy phosphoramidates with complementary RNA strands are not substrates for RNase H-mediated cleavage in vitro. Oligonucleotide phosphoramidates and especially thio -phosphoramidates conjugated with lipid groups are cell-permeable and demonstrate high biological target specific activity in vitro. In vivo, these compounds show good bioavailability and efficient biodistribution to all major organs, while exerting acceptable toxicity at therapeutically relevant doses. Short oligonucleotide N3,,P5, thio -phosphoramidate conjugated to 5,-palmitoyl group, designated as GRN163L (Imetelstat), was recently introduced as a potent human telomerase inhibitor. GRN163L is not an antisense agent; it is a direct competitive inhibitor of human telomerase, which directly binds to the active site of the enzyme and thus inhibits its activity. This compound is currently in multiple Phase-I and Phase-I/II clinical trials as potential broad-spectrum anticancer agent. [source]

Telomerase activity as a potential marker in preneoplastic bladder lesions

BJU INTERNATIONAL, Issue 4 2000
F. Lancelin
Objective To assess telomerase activity (involved in cell immortalization and detectable in most malignant tumours but not in normal somatic tissues) as a marker in cancer diagnosis. Patients and methods Tissue telomerase activity was assayed by two different techniques, the telomeric repeat amplification protocol-polymerase chain reaction (TRAP-PCR) and a telomerase PCR-enzyme linked immunosorbent assay. Malignant and inflammatory bladder lesions and their adjacent normal tissues were assessed for telomerase activity in a group of 18 patients, 14 of whom had urothelial carcinoma and four a nonspecific inflammatory lesion of the bladder. Results Eleven of the 14 tumour samples analysed were telomerase-positive and two of the three telomerase-negative tumour samples had a detectable ,telomerase inhibitor'. In the apparently normal tissues next to bladder tumours, four of the 14 specimens were telomerase-positive. Interestingly, these lesions were always next to high-grade muscle-invasive bladder tumours (pT2G3). Two of the four nonspecific inflammatory lesions (one of cystitis glandularis and one of severe dysplasia), known to be preneoplastic lesions, were also telomerase-positive. Conclusion These results strongly suggest that the reactivation of telomerase may be an early event in bladder carcinogenesis, preceding morphological changes related to malignant transformation. Telomerase activity may therefore be useful both as an indicator of malignant potential in preneoplastic lesions, e.g. cystitis glandularis and severe dysplasia, and as a prognostic marker of bladder tumour relapse or progression. [source]

Telomerase enzyme inhibition (TEI) and cytolytic therapy in the management of androgen independent osseous metastatic prostate cancer

THE PROSTATE, Issue 6 2010
Yingming Li
Abstract BACKGROUND Recurrent prostate cancer can be osseous, androgen independent and lethal. The purpose is to discern the efficacy of synthetic small molecule telomerase enzyme inhibitors (TEI) alone or in combination with other cytotoxic therapies in controlling metastatic osseous prostate cancer. METHODS C4-2B was pre-treated with a match or mismatch TEI for 6 weeks and then inoculated into nude mice subcutaneously or intraosseously. In a separate experiment, untreated C4-2B was injected into femur of nude mice. The mice were divided into seven systemic "combination" treatment groups of control, Ad-BSP-E1a virus, docetaxel, mismatch and match TEI. Serum PSA was followed longitudinally. Histology analyses and histomorphometry were performed. Repeated measure analysis was applied for statistical analysis and Bonferroni method was used in multiple comparisons. RESULTS In the pre-treated study, the PSA of match treated cells in subcutaneous or intraosseous model was significantly lower than mismatch TEI or PBS treated group (P,<,0.05). Histology revealed increased fibrosis, apoptosis and decreased PSA staining in the match TEI treated subcutaneous xenografts. In the combination treatment study, the PSA was significantly lower in single/double treatment and triple treatment than control (P,<,0.05). Histology revealed that triple therapy mice had normal femur architecture. Histomorphometrics revealed that the area of femur tumor and woven bone was significantly positively correlated (P,=,0.007). CONCLUSIONS Multiple lines of data point toward the efficacy of systemically administered telomerase inhibitors. Combining cytotoxic regimens with telomerase inhibitors could be beneficial in controlling prostate cancer. Clinical trials are warranted to explore the efficacy of TEI in prostate cancer. Prostate 70: 616,629, 2010. © 2009 Wiley-Liss, Inc. [source]