11 research outputs found
Fundulus as the premier teleost model in environmental biology : opportunities for new insights using genomics
Author Posting. © Elsevier B.V., 2007. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Comparative Biochemistry and Physiology Part D: Genomics and Proteomics 2 (2007): 257-286, doi:10.1016/j.cbd.2007.09.001.A strong foundation of basic and applied research documents that the estuarine fish Fundulus heteroclitus and related species are unique laboratory and field models for understanding how individuals and populations interact with their environment. In this paper we summarize an extensive body of work examining the adaptive responses of Fundulus species to environmental conditions, and describe how this research has contributed importantly to our understanding of physiology, gene regulation, toxicology, and ecological and evolutionary genetics of teleosts and other vertebrates. These explorations have reached a critical juncture at which advancement is hindered by the lack of genomic resources for these species. We suggest that a more complete genomics toolbox for F. heteroclitus and related species will permit researchers to exploit the power of this model organism to rapidly advance our understanding of fundamental biological and pathological mechanisms among vertebrates, as well as ecological strategies and evolutionary processes common to all living organisms.This material is based on work supported by grants from the National Science Foundation DBI-0420504 (LJB), OCE 0308777 (DLC, RNW, BBR), BES-0553523 (AW), IBN 0236494 (BBR), IOB-0519579 (DHE), IOB-0543860 (DWT), FSML-0533189 (SC); National Institute of Health NIEHS P42-ES007381(GVC, MEH), P42-ES10356 (RTD), ES011588 (MFO); and NCRR P20 RR-016463 (DWT); Natural Sciences and Engineering Research Council of Canada Discovery (DLM, TDS, WSM) and Collaborative Research and Development Programs (DLM); NOAA/National Sea Grant NA86RG0052 (LJB), NA16RG2273 (SIK, MEH,GVC, JJS); Environmental Protection Agency U91620701 (WSB), R82902201(SC) and EPA’s Office of Research and Development (DEN)
Glycosidation Route to 4''-epi-(Methylamino)-4''-Deoxyavermectin B1 (MK-244, Emamectin Benzoate)
Asymmetric Synthesis of Cyclic Hydroxy Ketones Derived from Enol Ethers via Sharpless Asymmetric Dihydroxylation. A Study in the Correlation of the Enol Ether Chain Length and Enantioselectivity
Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation
Development of a practical asymmetric synthesis of a
glucagon receptor
antagonist drug candidate for the treatment of type 2 diabetes is
described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane
core substituted with a propyl and three aryl groups including a fluoro-indole.
The key steps to construct the ethane core and the two stereogenic
centers involved a ketone arylation, an asymmetric hydrogenation via
dynamic kinetic resolution, and an <i>anti</i>-selective
Friedel–Crafts alkylation of a fluoro-indole with a chiral
α-phenyl benzyl cation. We also developed two new efficient
syntheses of the fluoro-indole, including an unusual Larock-type indole
synthesis and a Sugasawa-heteroannulation route. The described convergent
synthesis was used to prepare drug substance in 52% overall yield
and 99% ee on multikilogram scales
Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation
Development of a practical asymmetric synthesis of a
glucagon receptor
antagonist drug candidate for the treatment of type 2 diabetes is
described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane
core substituted with a propyl and three aryl groups including a fluoro-indole.
The key steps to construct the ethane core and the two stereogenic
centers involved a ketone arylation, an asymmetric hydrogenation via
dynamic kinetic resolution, and an <i>anti</i>-selective
Friedel–Crafts alkylation of a fluoro-indole with a chiral
α-phenyl benzyl cation. We also developed two new efficient
syntheses of the fluoro-indole, including an unusual Larock-type indole
synthesis and a Sugasawa-heteroannulation route. The described convergent
synthesis was used to prepare drug substance in 52% overall yield
and 99% ee on multikilogram scales
Practical Asymmetric Synthesis of a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant
The development of
a scalable asymmetric route to a new calcitonin
gene-related peptide (CGRP) receptor antagonist is described. The
synthesis of the two key fragments was redefined, and the intermediates
were accessed through novel chemistry. Chiral lactam <b>2</b> was prepared by an enzyme mediated dynamic kinetic transamination
which simultaneously set two stereocenters. Enzyme evolution resulted
in an optimized transaminase providing the desired configuration in
>60:1 <i>syn</i>/<i>anti</i>. The final chiral
center was set via a crystallization induced diastereomeric transformation.
The asymmetric spirocyclization to form the second fragment, chiral
spiro acid intermediate <b>3</b>, was catalyzed by a novel doubly
quaternized phase transfer catalyst and provided optically pure material
on isolation. With the two fragments in hand, development of their
final union by amide bond formation and subsequent direct isolation
is described. The described chemistry has been used to deliver over
100 kg of our desired target, ubrogepant