The easily accessible C-nucleoside
2-amino-5-(2‘-deoxy-β-d-ribofuranosyl)pyridine
(P) and its 3-methyl
(
Me
P) and 2‘-O-methyl
(P
OMe
) derivatives were synthesized
and incorporated as protonated cytidine equivalents in
homopyrimidine oligodeoxynucleotides. T
m
measurements indicate that oligonucleotides containing P or
Me
P have
a higher affinity to double-stranded DNA over the pH range of 6−8
than 5-methylcytidine (MeC) containing
oligonucleotides. This increase in stability is most pronounced
above pH 7.0. The average increase in
T
m/modification
for the dissociation of oligonucleotide
d(TTTTTMePTMePTMePTMePTMePT)
from a 21-mer target duplex at pH 7.5 is
2.3 °C relative to oligonucleotide
d(TTTTTMeCTMeCTMeCTMeCTMeCT).
The pH dependence and sequence
composition effects are much less pronounced for
Me
P (and also P)
containing oligonucleotides than for MeC
containing
ones. While oligonucleotide
d(TTTMeCMeCMeCMeCTTTTMeCTTT)
shows no longer any affinity to the target duplex
above pH 6.5, oligonucleotide
d(TTTMePMePMePMePTTTTMePTTT)
displays preserved binding with a T
m of 32.5
°C
at pH 7.0 and even binds with a T
m of 23.3 °C
at pH 8.0. Oligonucleotides containing
P
OMe
show distinctly
less
stable triple helices. The average decrease in
T
m/modification for oligonucleotide
d(TTTTTPOMeTPOMeTPOMeTPOMeTPOMeT) at pH 6.5 is 6.7 °C relative to the
MeC containing oligonucleotide. DNase I footprint
titration experiments
indicate that
d(TTTTTMePTMePTMePTMePTMePT)
binds not only five times stronger to a 229 base pair DNA
fragment
than
d(TTTTTMeCTMeCTMeCTMeCTMeCT)
but also with higher selectivity. UV-melting experiments show
that
duplexes of d(TTTTTCTXTCTCTCT) (where X = P,
Me
P, or
P
OMe
) with their antiparallel
Watson−Crick complement
are dramatically less stable (ΔT
m < −12
°C) at pH 8.0 than the corresponding natural duplex. Thus the
new bases
P and
Me
P show Hoogsteen
specific pairing behavior.
The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.
A short and high-yielding synthesis of carmegliptin (1) suitable for large-scale production is reported. The tricyclic core was assembled efficiently by a decarboxylative Mannich addition−Mannich cyclization sequence. Subsequent crystallization-induced dynamic resolution of enamine 7 using (S,S)-dibenzoyltartaric acid was followed by diastereoselective enamine reduction to give the fully functionalized tricyclic core with its three stereogenic centers. The C-3 nitrogen was introduced by Hofmann rearrangement of amide 28, and the resulting amine 10 was coupled with (S)-fluoromethyl lactone 31. Following cyclization to lactam 13 and amine deprotection, 1 was obtained in 27−31% overall yield with six isolated intermediates.
COMMUNICATIONSover MgSO, and concentrated under reduced pressure. After separation by column chromatography (silica gel, hexane:EtOAc = 20:1), 12b (20mg. 0.11 mmol) and 13b (56 mg, 0.30 mmol) were isolated in 21 and 60% yield, respectively. as colorless oils.12b;'HNMR(30OMHz,CDCI3):6 =1.03(s,3H).2.19(dd,J=l5.0,7.
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