Amino Amide Organocatalysts for Asymmetric Michael Addition of β-Keto Esters with β-Nitroolefins

Asymmetric Michael addition of β-keto esters with trans-β-nitroolefins using chiral amino amide organocatalyst was tried and afforded synthetically useful chiral Michael adducts in both excellent chemical yields (up to 99%) and stereoselectivities (up to dr. 99:1, up to 98% ee)

HIV-1 nef suppression by virally encoded microRNA

BACKGROUND: MicroRNAs (miRNAs) are 21~25-nucleotides (nt) long and interact with mRNAs to trigger either translational repression or RNA cleavage through RNA interference (RNAi), depending on the degree of complementarity with the target mRNAs. Our recent study has shown that HIV-1 nef dsRNA from AIDS patients who are long-term non-progressors (LTNPs) inhibited the transcription of HIV-1. RESULTS: Here, we show the possibility that nef-derived miRNAs are produced in HIV-1 persistently infected cells. Furthermore, nef short hairpin RNA (shRNA) that corresponded to a predicted nef miRNA (~25 nt, miR-N367) can block HIV-1 Nef expression in vitro and the suppression by shRNA/miR-N367 would be related with low viremia in an LTNP (15-2-2). In the 15-2-2 model mice, the weight loss, which may be rendered by nef was also inhibited by shRNA/miR-N367 corresponding to suppression of nef expression in vivo. CONCLUSIONS: These data suggest that nef/U3 miRNAs produced in HIV-1-infected cells may suppress both Nef function and HIV-1 virulence through the RNAi pathway

Hybrid-Type Squaramide-Fused Amino Alcohol Organocatalysts for Enantioselective Nitro-Aldol Reaction of Nitromethane with Isatins

A series of new hybrid type squaramide-fused amino alcohol (SFAA) catalysts were synthesized and their catalytic efficiency in enantioselective nitro-aldol reaction of various isatins with nitromethane that afford the chiral 3-substituted 3-hydroxyoxindoles in excellent chemical yields (up to 99%) and high enantioselectivities (up to 95% ee) is described. The resulting chiral 3-hydroxyoxindoles could be used as synthetic precursors for the synthesis of several natural products with a broad spectrum of fascinating biological activities

Chiral primary amino alcohol organobase catalyst for the asymmetric Diels-Alder reaction of anthrones with maleimides

Simple chiral TES-amino alcohol organocatalysts containing a bulkysilyl [triethylsilyl: TES] group on oxygen atom at γ-position were designed andsynthesized as new organocatalysts for the enantioselective Diels-Alder (DA) reactionof anthrones with maleimides to produce chiral hydroanthracene DA adducts (up to99% yield with up to 94% ee)

Disease-Association Analysis of an Inflammation-Related Feedback Loop

SummaryThe IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets

BRCAness Predicts Resistance to Taxane-Containing Regimens in Triple Negative Breast Cancer During Neoadjuvant Chemotherapy

AbstractBackgroundTo provide optimal treatment of heterogeneous triple negative breast cancer (TNBC), we need biomarkers that can predict the chemotherapy response.Patients and MethodsWe retrospectively investigated BRCAness in 73 patients with breast cancer who had been treated with taxane- and/or anthracycline-based neoadjuvant chemotherapy (NAC). Using multiplex, ligation-dependent probe amplification on formalin-fixed core needle biopsy (CNB) specimens before NAC and surgical specimens after NAC. BRCAness status was assessed with the assessor unaware of the clinical information.ResultsWe obtained 45 CNB and 60 surgical specimens from the 73 patients. Of the 45 CNB specimens, 17 had BRCAness (38.6% of all subtypes). Of the 23 TNBC CNB specimens, 14 had BRCAness (61% of TNBC cases). The clinical response rates were significantly lower for BRCAness than for non-BRCAness tumors, both for all tumors (58.8% vs. 89.3%, P = .03) and for TNBC (50% vs. 100%, P = .02). All tumors that progressed with taxane therapy had BRCAness. Of the patients with TNBC, those with non-BRCAness cancer had pathologic complete responses significantly more often than did those with BRCAness tumors (77.8% vs. 14.3%, P = .007). After NAC, the clinical response rates were significant lower for BRCAness than for non-BRCAness tumors in all subtypes (P = .002) and in TNBC cases (P = .008). After a median follow-up of 26.4 months, 6 patients—all with BRCAness—had developed recurrence. Patients with BRCAness had shorter progression-free survival than did those with non- BRCAness (P = .049).ConclusionIdentifying BRCAness can help predict the response to taxane, and changing regimens for BRCAness TNBC might improve patient survival. A larger prospective study is needed to further clarify this issue

New Hybrid-type Squaramide-Fused Amino Alcohol Organocatalyst for Enantioselective Domino Michael Addition/Cyclization Reaction of Oxoindolines with Cyclic 1,3-Diketones

The new hybrid-type squaramide-fused amino alcohol containing both a Bronsted basic site and hydrogen bondingsites in the molecule showed a high catalytic activity as an l organocatalyst in the enantioselective domino Michael addition/cyclization reaction of oxoindohnes with cyclic 1,3-etones to afford\u27the chiralsproonjugate oxindoles featuring 2-aminopyrans fusing with l carbo-heterocyclic ring systems with l excellent chemical yields (up Ito 98%) and enantioselectivities (up to 95% ee). The obtained chiral spiroconjugated 2-aminopyrans bearing quaternary stereogenic carbon center could be used as l synthetic precursors for several natural products that ave a broad spectrum Iof fascinating biological activities

Biotransformation of organic compounds in vivo using larvae of beetles (Allomyrina dichotoma) as biocatalysts

The biotransformation of organic compounds using the larvae of the Japanese rhinoceros beetle (Allomyrina dichotoma) as a biocatalyst is described. When phenyl alkanediones were administered by mouth (p.o) or subcutaneous injection (s.c) to the beetle, asymmetric reduction occurred to yield the corresponding diols in varying optical yields: 1-phenyl-1,2-propandione or 1-phenyl-1,3-butanedione reduced to (1R,2S)- and (1S,2S)-1,2-phenylpropanediols in high optical yields or (1R,3S)- and (1R,3R)-1-phenyl-1,3-butanediols in low to high optical yields, respectively. By administrating 1-phenyl-1-propanone, 1-phenyl-1-butanone or 4-phenyl-2-butanone, redox reactions occurred to give 1-phenyl-1,2-propanediols or 1-phenyl-1,3-butanediols in lower optical yields. The administrations of β-ionone and cinnamyl chloride resulted in regioselective allylic oxidations producing enone and cinnamic acid, respectively. However, when (R)-(-)-carvone was administered, regiospecific dihydroxylation at the isopropenyl group occurred to give (4R,8R)- and (4R,8S)-8,9-dihydroxy-8,9-dihydrocarvone as diastereoisomers. These results appear to demonstrate similar reaction tendency with the case of a microorganism. It is possible that these reactions were due in part to bacteria in the intestine of the larva: however, regio- and stereoselectivities of the reactions were sometimes unique. Thus, it is supposed that these biotransformations were accomplished by the ensemble of the larva׳s own enzymes with several bacteria. The results obtained in this study might show the possibility of using such enzymes derived from insects, including beetle larvae, as a biocatalyst