Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and induces ATF4 translation through delayed re-initiation.

ATF4 is a pro-oncogenic transcription factor whose translation is activated by eIF2 phosphorylation through delayed re-initiation involving two uORFs in the mRNA leader. However, in yeast, the effect of eIF2 phosphorylation can be mimicked by eIF5 overexpression, which turns eIF5 into translational inhibitor, thereby promoting translation of GCN4, the yeast ATF4 equivalent. Furthermore, regulatory protein termed eIF5-mimic protein (5MP) can bind eIF2 and inhibit general translation.

Mechanisms by which synthetic 6,7-annulated-4-substituted indole compounds with anti-proliferative activity disrupt mitosis and block cytokinesis in human HL-60 tumor cells in vitro.

Background: Synthetic 6,7-annulated-4-substituted indole compounds, which elicit interesting antitumor effects in murine L1210 leukemia cells, were tested for their ability to inhibit human HL-60 tumor cell proliferation, disrupt mitosis and cytokinesis, and interfere with tubulin and actin polymerization in vitro.

Materials And Methods: Various markers of metabolic activity, mitotic disruption and cytokinesis were used to assess the effectiveness of the drugs in the HL-60 tumor cell system. The ability of annulated indoles to alter the polymerizations of purified tubulin and actin were monitored in cell-free assays and were compared to the effects of drugs known to disrupt the dynamic structures of the mitotic spindle and cleavage furrow.

Antitumor effects of synthetic 6,7-annulated-4-substituted indole compounds in L1210 leukemic cells in vitro.

Background: Because annulated indoles have almost no representation in the PubChem or MLSMR databases, an unprecedented class of an indole-based library was constructed, using the indole aryne methodology, and screened for antitumor activity. Sixty-six novel 6,7-annulated-4-substituted indole compounds were synthesized, using a strategic combination of 6,7-indolyne cycloaddition and cross-coupling reactions under both Suzuki-Miyaura and Buchwald-Hartwig conditions, and tested for their effectiveness against murine L1210 tumor cell proliferation in vitro.

Materials And Methods: Various markers of tumor cell metabolism, DNA degradation, mitotic disruption, cytokinesis and apoptosis were assayed in vitro to evaluate drug cytotoxicity.

Bioactivity of synthetic 2-halo-3-aryl-4(3H)-quinazoliniminium halides in L1210 leukemia and SK-BR-3 mammary tumor cells in vitro.

Background: Because quinazolines and their derivatives exhibit a wide range of pharmacological profiles, there is a continuous interest among synthetic and medicinal chemists in the discovery of more potent analogs. Ten novel quinazoliniminium salts were synthesized and tested for their effectiveness against murine and human tumor cell proliferation in vitro.

Materials And Methods: Various markers of tumor cell metabolism, DNA degradation and mitotic disruption were assayed in vitro to evaluate drug cytotoxicity.

Synthesis and antiproliferative evaluation of 5-oxo and 5-thio derivatives of 1,4-diaryl tetrazoles.

A series of 1,4-diaryl tetrazol-5-ones were synthesized by copper mediated N-arylation of 1-phenyl-1H-tetrazol-5(4H)-one with aryl boronic acids, o-R(1)C(6)H(4)B(OH)(2) where R(1)=H, OMe, Cl, CF(3), Br, CCH. The 1,4-diaryl tetrazol-5-ones substituted with OMe, Cl, CF(3), Br underwent thionation with Lawesson's reagent to yield the corresponding 5-thio derivatives. The 1-(2-bromophenyl)-4-phenyl-1H-tetrazole-5(4H)-thione so obtained was subjected to lithiation/protonation and Sonogashira coupling to produce 1,4-diphenyl-1H-tetrazole-5(4H)-thione and 1-(2-ethynylphenyl)-4-phenyl tetrazole-5-thione, respectively.