The 5′-AT-rich half-site of Maf recognition element: a functional target for bZIP transcription factor Maf

The Maf family of proteins are a subgroup of basic region-leucine zipper (bZIP) transcription factors, which recognize a long palindromic DNA sequence [TGCTGAC(G)TCAGCA] known as the Maf recognition element (MARE). Interestingly, the functional target enhancer sequences present in the αA-crystallin gene contain a well-conserved half-site of MARE rather than the entire palindromic sequence. To resolve how Maf proteins bind to target sequences containing only MARE half-sites, we examined their binding activities using electrophoretic gel mobility shift assays as well as in vitro and in vivo reporter assays. Our results indicate that the 5′-flanking region of the MARE half-site is required for Maf proteins to bind both in vitro and in vivo. The critical 5′-flanking sequences for c-Maf were determined by a selection and amplification binding assay and show a preference for AT-rich nucleotides. Furthermore, sequence analysis of the regulatory regions of several target genes also suggests that AT-rich sequences are important. We conclude that Maf can bind to at least two types of target sequences, the classical MARE (palindrome type) and a 5′-AT-rich MARE half-site (half-site type). Our results provide important new insights into the DNA binding and site selection by bZIP transcription factors

Total synthesis of (±)-stemonamide, (±)-isostemonamide, (±)-stemonamine, and (±)-isostemonamine using a radical cascade

金沢大学医薬保健研究域薬学系A total synthesis of (±)-stemonamide and (±)-isostemonamide has been achieved by using a radical cascade that involves two endo-selective cyclizations. (±)-Stemonamine and (±)-isostemonamine are synthesized by chemoselective reduction of (±)-stemonamide and (±)-isostemonamide, respectively. © 2008 Elsevier Ltd. All rights reserved

Novel synthesis of 3-aminopropionitriles by ring opening of 2-oxazolidinones with cyanide ion

金沢大学医薬保健研究域薬学系Nucleophilic attack of cyanide ion on the 5-position of 2-oxazolidinones in the presence of 18-crown-6 gave 3-aminopropionitriles. © 2009 Elsevier Ltd. All rights reserved

Role of 1,4-dimethylpiperazine in radical cyclizations

金沢大学医薬保健研究域薬学系Radical cyclization of o-ethenyltrichloroacetanilides in boiling 1,4-dimethylpiperazine was examined with a comparison of the mode of radical cyclizations under a Bu3SnH-mediated condition. It was found that an attack of a hydrogen atom on the cyclized radical intermediates occurred more rapidly in 1,4-dimethylpiperazine than under the Bu3SnH-mediated condition. This phenomenon was also observed in similar reactions of N- ethenyltrichloroacetamide. ©ARKAT USA, Inc

Synthesis of (-)-trachelanthamidine using a single electron transfer reaction in 1,4-dimethylpiperazine

金沢大学医薬保健研究域薬学系Synthesis of (-)-trachelanthamidine, one of the pyrrolizidine alkaloids, has been achieved by using a single electron transfer reaction of 2-(2-acetoxyethenyl)-N-(trichloroacetyl)pyrrolidine in boiling 1,4-dimethylpiperazine as the key step. © 2008 Elsevier Ltd. All rights reserved

Water in amine-mediated single electron transfer reaction of N-allylic trichloroacetamides

金沢大学医薬保健研究域薬学系Water contaminating 1,4-dimethylpiperazine was thought to play an important role in effecting a single electron transfer reaction (radical cyclization) of N-allylic trichloroacetamides. © 2010 The Japan Institute of Heterocyclic Chemistry

8-Endo-selective aryl radical cyclization leading to 3-benzazocines

金沢大学医薬保健研究域薬学系Bu3SnH-mediated radical cyclization of N-acyl-3-(2-bromophenyl)-N-ethenypropylamines (14) occurred in an endo-selective manner to give the 3-benzazocine derivatives (15) in good yields. © 2009 The Japan Institute of Heterocyclic Chemistry All rights reserved

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

金沢大学大学院自然科学研究科生理活性物質科学The effect of positional change of the carbonyl group of enamides on Bu3SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides. © 2008 Elsevier Ltd. All rights reserved

Identification of a phenanthrene derivative as a potent anticancer drug with Pim kinase inhibitory activity

Pim-3, a proto-oncogene with serine/threonine kinase activity, is aberrantly expressed in malignant lesions, but not in normal tissues, of endoderm-derived organs, including the pancreas, liver, colon, and stomach. Furthermore, the development of hepatocellular carcinoma is accelerated in mice expressing Pim-3 transgene selectively in the liver when these mice are treated with a hepatocarcinogen. These observations suggest that a chemical targeting Pim-3 kinase may be a novel type of anticancer drug. In the present study, we screened low molecular weight chemicals and observed that the phenanthrene derivative T26 potently inhibited Pim-3 and Pim-1, but only weakly inhibited Pim-2. Moreover, T26 markedly inhibited the in vitro growth of human pancreatic cancer cell lines by inducing apoptosis and G 2/M arrest. The growth inhibitory effects of T26 were reversed by overexpression of Pim-3 cDNA in human pancreatic cancer cells, indicating that T26 acts primarily on Pim-3. Furthermore, T26 inhibited the growth of a human pancreatic cancer cell line in nude mice without causing apparent adverse effects when it was administered after tumor formation was evident. These observations imply that the chemical and its related compounds may be effective for the treatment of cancers in which there is aberrant Pim-3 expression. © 2011 Japanese Cancer Association