Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Schram Family of Wainfleet Township documents, 1839-1901 (not inclusive)

George William Schram (1809-1885), son of Garrett Schram and Leah Van Etten, married Orpha Pearson on Nov.13, 1835. His son Marsena John Schram (farmer) was born in May of 1840, in Canada. He died on Nov. 17, 1926 in Wexford County, Michigan. He was married in 1867 to Sarah (1825-1887).Marsena married again on April 18, 1910 to Ann Clarinda Warner (1861-1924). He was working as a carpenter at this time. They had another son, William who was born about 1838 and he married Sabina Chambers on Jan. 21, 1862. The 1861 census for Wainfleet lists siblings of Marsena John Schram as Sarah J. (age 14), Georgiana (age 5), and William (age 21). The Schrams lived on Concession 5 and owned approximately 144 acres of land. David Thompson was born Feb. 4, 1873 and died Feb. 19, 1951. He married Sally Ann Wilson on Sept. 7, 1825 in Pelham. She died about 1840 in Indiana Ontario (near Cayuga). Lemuel Victor Hogue was born Dec.1, 1854 and died Jan. 12, 1929. He was married to Elizabeth Wills who was born Aug. 2, 1861 and died Mar. 8, 1926. Sources: http://www.findagrave.com/cgi-bin/fg.cgi?page=gr&GRid=99294842 http://wc.rootsweb.ancestry.com/cgi-bin/igm.cgi?op=GET&db=seadragon5&id=I91708

The γ-tocopherol-like family of N-methyltransferases: A taxonomically clustered gene family encoding enzymes responsible for N-methylation of monoterpene indole alkaloids

The plant family Apocynaceae accumulates thousands of monoterpene indole alkaloids (MIAs) which originate, biosynthetically, from the common secoiridoid intermediate, strictosidine, that is formed from the condensation of tryptophan and secologanin molecules. MIAs demonstrate remarkable structural diversity and have pharmaceutically valuable biological activities. For example; a subunit of the potent anti-neoplastic molecules vincristine and vinblastine is the aspidosperma alkaloid, vindoline. Vindoline accumulates to trace levels under natural conditions. Research programs have determined that there is significant developmental and light regulation involved in the biosynthesis of this MIA. Furthermore, the biosynthetic pathway leading to vindoline is split among at least five independent cell types. Little is known of how intermediates are shuttled between these cell types. The late stage events in vindoline biosynthesis involve six enzymatic steps from tabersonine. The fourth biochemical step, in this pathway, is an indole N-methylation performed by a recently identified N-methyltransfearse (NMT). For almost twenty years the gene encoding this NMT had eluded discovery; however, in 2010 Liscombe et al. reported the identification of a γ-tocopherol C-methyltransferase homologue capable of indole N-methylating 2,3-dihydrotabersonine and Virus Induced Gene Silencing (VIGS) suppression of the messenger has since proven its involvement in vindoline biosynthesis. Recent large scale sequencing initiatives, performed on non-model medicinal plant transcriptomes, has permitted identification of candidate genes, presumably involved, in MIA biosynthesis never seen before in plant specialized metabolism research. Probing the transcriptome assemblies of Catharanthus roseus (L.)G.Don, Vinca minor L., Rauwolfia serpentine (L.)Benth ex Kurz, Tabernaemontana elegans, and Amsonia hubrichtii, with the nucleotide sequence of the N-methyltransferase involved in vindoline biosynthesis, revealed eight new homologous methyltransferases. This thesis describes the identification, molecular cloning, recombinant expression and biochemical characterization of two picrinine NMTs, one from V. minor and one from R. serpentina, a perivine NMT from C. roseus, and an ajmaline NMT from R. serpentina. While these TLMTs were expressed and functional in planta, they were active at relatively low levels and their N-methylated alkaloid products were not apparent our from alkaloid isolates of the plants. It appears that, for the most part, these TLMTs, participate in apparently silent biochemical pathways, awaiting the appropriate developmental and environmental cues for activity.

Composite Photographs - Woodruff Family of St. Davids, Upper Canada

Composite of the Woodruff Family of St. Davids, Upper Canada. This composite contains 6 4 ½ cm x 4 cm black and white photographs which include: Samuel DeVeaux Woodruff (1819-1904) [the birth and death dates listed on this composite are 1827-1912, but these are actually his wife’s dates] son of William Woodruff. Joseph Woodruff (1820-1882) [1820-1886] son of William Woodruff. Helena Woodruff (1828-1892) daughter of William Woodruff. Julia Woodruff (1825-1870) daughter of William Woodruff. Dr. William Woodruff (1830-1908) son of William Woodruff. Margaret Clements [Clement] Woodruff (1794-1882) wife of William Woodruff

Genealogical and Historical Sketch of the Name and Family of Woodruff

Genealogical and Historical Sketch of the name and family of Woodruff compiled by the Media Research Bureau of Washington, D.C. This document traces the Woodruff name to its Anglo-Saxon origins and lists members of the family who have distinguished themselves in America in more recent times, n.d.

Structural bioinformatics analysis of the family of human ubiquitin-specific proteases

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Systematics and biology of Fishes of family of the hemiramphidae of Cochin coast

This overall focus of the thesis involves the systematics and biology of fishes of the family hemiramphidae of cochin coast.India is one of the leading fish producing nations in the world with an average annual production of 6.1 million tonnes of fish and shell fish from capture and culture fisheries in 2001 (Ayyappan and Biradar, 2002).Fisheries play a very significant role in the Indian economy by providing employment to nearly 7 million people directly or indirectly, supplying rich protein food and earning valued foreign exchange.Fishes of the family Hemiramphidae are commonly called ‘half beaks‘.In India, studies on hemiramphids commenced with the work of Day (1878,1889) who recorded thirteen species of hemiramphids from the Indian waters.The study area, which is part of Cochin coast is located between Lat.9°28’ and 10° N and Long.76° 13’ and 76° 31 E. Lying parallel to it is an estuary which is commonly called the Cochin backwaters which has a total area of about 200 sq.miles.The study area is subjected to wide variations in salinity from place to place, season and surface to bottom.The Cochin coast and the adjacent back water system of Kerala has a rich and diversified fish fauna. The hemiramphid fishes constitute a minor fishery of this area.The study on the distribution and availability of hemiramphid fishes present in the Cochin coast shows that they evince different patterns of distribution.In the present study it is noticed that fecundity has high correlation with weight than length of the fish.Histological studies revealed that the spermatogenesis in both H. (H) limbatus and H.(H) xanthopterus, consists of spermatogonia, primary spermatocytes secondary, spermatocytes, spermatids and spermatozoa whereas in the oogenesis of both the species.biological study will be useful in implementation of proper measures of conservation and management so that further devastation of the hemiramphids of Cochin Coast can be controlled.

Spin-Peierls vs Peierls distortions in a family of conjugated polymers

Distortions in a family of conjugated polymers are studied using two complementary approaches: within a many-body valence bond approach using a transfer-matrix technique to treat the Heisenberg model of the systems, and also in terms of the tight-binding band-theoretic model with interactions limited to nearest neighbors. The computations indicate that both methods predict the presence or absence of the same distortions in most of the polymers studied.