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A simple and efficient procedure for the synthesis of thiol esters 3 has been developed by utilizing carbonyl sulfide (S=C=O, 1) as a thiocarboxylation agent. Treatment of 1 with organolithium reagents at-78 °C for 5 min yielded lithium thiocarboxylates 2. Trapping of 2 with alkyl iodides gave the corresponding thiol esters 3 in good to excellent yields. Similarly, the reaction of 1 with cyanoarylcuprates followed by alkylation under similar conditions afforded 3. [ABSTRACT FROM AUTHOR]

Human telomerase is a reverse transcriptase that is expressed in essentially all cancer cells, but not in the vast majority of normal somatic cells. Therefore, the specific inhibition of telomerase activity in tumors might have significant beneficial therapeutic effects. We have designed and evaluated oligonucleotide N3′ → P5′ thio-phosphoramidates as telomerase template antagonists. In biochemical cell-free assays 11-13-mer thio-phosphoramidate oligonucleotides demonstrated sequence specific and dose dependent inhibition of telomerase with pico-molar IC50 values. Optimization of the oligonucleotide sequence and length resulted in the identification of a 13-mer-oligonucleotide thio-phosphoramidate GRN163 as a drug development candidate. In cell cultures GRN163 was able to inhibit telomerase activity in the absence of cationic lipid with ∼1 µM IC50 values. Telomerase inhibition by GRN163 produced gradual telomere shortening, followed by cellular senescence and/or apoptosis of cancer derived cell lines. [ABSTRACT FROM AUTHOR]

Despite major advances in curative and palliative approaches, hepatocellular carcinoma (HCC) is still the third leading cause of cancer-related death worldwide. M1 macrophages (Mφ) play a key role in host antitumor defenses in HCC. In our study, CD14+cells were isolated from the peripheral blood of four groups of HCC patients (group-1, patients with stage 0 HCC; group-2, patients with stage A HCC; group-3, patients with stage B HCC; and group-4, patients with stage C HCC) and characterized phenotypically. Then, CD14+cells from group-2 and group-3 HCC patients were induced to polarize and tested for their antitumor abilities in a chimera model of HCC patients. Human HCCs (HepG2 solid tumors) grew in a chimera model of group-3 patients (group-3 HCC chimeras) but not in a chimera model of group-2 patients (group-2 HCC chimeras). In response to HCC antigens, the majority of CD14+cells from group-2 patients (group-2 CD14+cells) switched to the M1 phenotype (IL-12+IL-10−iNOS+cells), whereas the majority of CD14+cells from group-3 patients (group-3 CD14+cells) did not switch to the M1 phenotype and continued to express M2b phenotypic properties (IL-12−IL-10+CCL1+iNOS−cells). Group-3 CD14+cells showed M1Mφ polarization after treatment with CCL1 antisense oligodeoxynucleotide (ODN). Therefore, our study indicates that anti-HCC defenses of group-3 HCC chimeras are improved after CCL1 antisense ODN treatment. [ABSTRACT FROM AUTHOR]

A set of new sulfurated drug hybrids, mainly derived from caffeic and ferulic acids and rosmaricine, has been synthesized and their ability to inhibit both STAT3 and NF-κB transcription factors have been evaluated. Results showed that most of the new hybrid compounds were able to strongly and selectively bind to STAT3, whereas the parent drugs were devoid of this ability at the tested concentrations. Some of them were also able to inhibit the NF-κB transcriptional activity in HCT-116 cell line and inhibited HCT-116 cell proliferationin vitrowith IC50in micromolar range, thus suggesting a potential anticancer activity. Taken together, our study described the identification of new derivatives with dual STAT3/NF-κB inhibitory activity, which may represent hit compounds for developing multi-target anticancer agents. [ABSTRACT FROM PUBLISHER]

With the aim to discover new STAT3 direct inhibitors, potentially useful as anticancer agents, a set of methanethiosulfonate drug hybrids were synthesized. Thein vitrotests showed that all the thiosulfonic compounds were able to strongly and selectively bind STAT3-SH2 domain, whereas the parent drugs were completely devoid of this ability. In addition, some of them showed a moderate antiproliferative activity on HCT-116 cancer cell line. These results suggest that methanethiosulfonate moiety can be considered a useful scaffold in the preparation of new direct STAT3 inhibitors. Interestingly, an unusual kind of organo-sulfur derivative, endowed with valuable antiproliferative activity, was occasionally isolated. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3) plays an essential role in cell growth regulation and survival. An aberrant STAT3 activation and/or expression is implied in various solid and blood tumors as well as in other pathologies like rheumatoid arthritis and pulmonary fibrosis, thus making the search for STAT3 inhibitors a growing field of study. With the aim of identifying new inhibitors of STAT3 dimerization, we screened a database including more than 1 320 000 commercially available compounds using a receptor-based pharmacophore model comprising the key protein–protein interactions identified in the STAT3 dimer and refining the search through docking and molecular dynamic simulations studies. STAT3 binding assays revealed a significant STAT3 inhibitory activity and selectivity versus Grb2 for one of the four top-scored compounds, thus verifying the reliability of the virtual screening workflow. Moreover, such compound could already be considered as a lead for the development of new and more potent STAT3 dimerization inhibitors. [ABSTRACT FROM PUBLISHER]