Epigenetic Evaluation of N-(2-hydroxyphenyl)-2-propylpentanamide, a Valproic Acid Aryl Derivative with activity against HeLa cells

Background: Valproic acid (VPA) is an HDAC inhibitor (HDACI) with anticancer activity, but it is hepatotoxic. N-(2-hydroxyphenyl)-2-propylpentanamide (o-OH-VPA) is a VPA aryl derivative designed in silico as a selective inhibitor of HDAC8 with biological properties against HeLa, rhabdomyosarcoma and breast cancer cell cultures. Objective: We studied the epigenetic mechanism of o-OH-VPA as an HDACI and we evaluated whether it was toxic to normal cells. Methods: HeLa cells and primary human fibroblast were used for this study as carcinogenic and normal cells, respectively. Cell survival was evaluated by MTT assay; viability and doubling time were determined by Trypan-blue method. HDAC activity was tested using the colorimetric HDAC activity assay. The expression of p21 was analyzed by PCR and HDAC8 expression was also evaluated by real-time PCR. Cell cycle and caspase-3 activity were analyzed by flow cytometry and caspase-3 colorimetric assay, respectively. Results: o-OH-VPA (IC50 = 0.1 mM) was fifty-eight more effective than VPA (IC50 = 5.8 mM) to reduce HeLa cell survival. Furthermore, o-OH-VPA increased the doubling time of HeLa cells by 33% with respect to the control. o-OHVPA acted as HDACI in HeLa cells without affecting the HDAC8 expression, arresting the cell cycle of HeLa cells in the G0/G1 phase due to the increase in p21 expression with inhibition of caspase-3 activity without exhibiting toxicity toward normal cells. Conclusion: Our results revealed that o-OH-VPA is an HDACI with a selective effect against HeLa cells but without the known toxicity exerted by most pan-HDACIs on normal cells.

Understanding Chemistry and Unique NMR Characters of Novel Amide and Ester Leflunomide Analogues

A series of diverse substituted 5-methyl-isoxazole-4-carboxylic acid amides, imide and esters of the formula (I) in which the benzene ring is mono or disubstituted was prepared. Spectroscopic and conformational examination was investigated and a new insight involving steric interference and interesting downfield deviation due to additional diamagnetic anisotropic effect of the amidic carbonyl group and the methine protons in 2,6-diisopropyl-aryl derivative (2) as a conformationaly restricted analogues Leflunomide was discussed. Individual substituent electronic effects through resonance of p-substituents and most stable conformation of compound (2) are discussed.

C–N Ring Construction: The Fujii/Ohno Synthesis of (–)-Quinocarcin

Tsutomu Katsuki of Kyushu University devised (Org. Lett. 2012, 14, 4658) a Ru catalyst for the enantioselective aziridination of vinyl ketones such as 1. David W.C. MacMillan of Princeton University added (J. Am. Chem. Soc. 2012, 134, 11400) 3 to the alkene 4 under single electron conditions to give 5 with high stereocontrol. Barry M. Trost of Stanford University effected (J. Am. Chem. Soc. 2012, 134, 4941) the Pd-catalyzed addition of 7 to an imine 6 to give the pyrrolidine 8. More recently, he used (J. Am. Chem. Soc. 2013, 135, 2459) this approach to construct pyrrolidines containing defined quaternary centers. Christoph Schneider of the Universität Liepzig employed (Org. Lett. 2012, 14, 5972) an organocatalyst to control the relative and absolute configuration not only of the nitrogen-containing ring, but also of the stereogenic center on the sidechain of the pyrrolidone 11. Wei Wang of Lanzhou University also used (Adv. Synth. Catal. 2012, 354, 2635) an organocatalyst to assemble the pyrrolidine 14bearing two stereogenic centers. Using a gold catalyst, Constantin Czekelius of the Freie Universität Berlin constructed (Angew. Chem. Int. Ed. 2012, 51, 11149) the pyrrolidine 16 having a defined quaternary center. Motomu Kanai of the University of Tokyo used (J. Am. Chem. Soc. 2012, 134, 17019) a Cu catalyst to prepare both pyrrolidines and piperidines by condensing the precursor protected aminal 17 with a ketone 18. Wolfgang Kroutil of the University of Graz effected (Angew. Chem. Int. Ed. 2012, 51, 6713) selective enzymatic reductive amination of the methyl ketone of 20 to give, after cyclization and hydrogenation, the 2,6-dialkyl piperidine 21. Ramakrishna G. Bhat of the Indian Institute of Science Education and Research showed (J. Org. Chem. 2012, 77, 11349) that the reductive cyclization of the amino acid derivative could proceed with high diastereoselectivity to give 23. Peter O’Brien of the University of York and Iain Coldham of the University of Sheffield prepared (J. Am. Chem. Soc. 2012, 134, 5300) both pyrrolidines and piperidines by metalation of an aryl derivative such as 24, followed by alkylation. Shital K. Chattopadhyay of the University of Kalyani cyclized (J. Org. Chem. 2012, 77, 11056) the nitrone 26 to 27 with high diastereoselectivity.

Diethynyl Aryl Derivatives for P-Channel and N-Channel Organic Field-Effect Transistors

Organic field-effect transistors (OFETs) consisted of vacuum-evaporated diethynyl aryl derivatives were prepared and the device characteristics were evaluated. The fabricated OFETs showed typical p-type characteristics for diethynyl naphthalene derivative with two end naphthyl groups. By optimizing the fabrication process, the device exhibited a high field-effect hole mobility up to 0.12 cm2V−1s−1 and a high on/off current ratio of 3.3×105. On the other hand, OFETs showed typical n-type characteristics for diethynyl aryl derivative with two end heptafluoronaphthyl groups. We have observed clear changes from p-channel to n-channel conductions in OFETs by chemically modifying diethynyl aryl derivatives.