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Regio- and Stereoselective Ring Opening of 2,3-Epoxyalcohols with Diethylaluminium Azide
No full textReactions of epoxyalcohols with Et2AlN3 take place at the epoxide C-3 leading to 3-azido-1,2-diols with regioselectivity higher than 25:1
Ring-Opening of Epoxyalcohols by Diethylaluminium Cyanide. Regio- and Stereoselective Synthesis of 1-Cyano-2,3-diols.
No full textDiethylaluminium cyanide is a convenient reagent for the C-3 selective ring-opening of 2,3 epoxyalcohol
Synthesis of a val-pro diaminodiol dipeptide isostere by epoxyamine cyclization
No full textThe base-catalyzed hydroazidation of alpha'-amino alpha,beta-unsaturated ketones with in situ generated hydrazoic acid was found to proceed with highstereoselectivity in favor of the syn product. The stereoselectivity is controlled by the configuration of the enone and syn/anti ratios up to 7:1were obtained with secondary and tertiary amines at low temperature. By this route the diamino alcohol core of HIV-PR inhibitors ritonavir andlopinavir was synthesized in 37% yield from phenylalanine
Epoxyalcohol Route to Hydroxyethylene Dipeptide Isosteres. Stereodivergent Synthesis of the Diaminoalcohol Core of Ritonavir and its C-2 Epimer.
No full textA stereoselective synthesis of hydroxyethylene dipeptide isosteres based on the 1,4-diamino-2-
hydroxybutane structure is described. Horner-Emmons olefination of phosphonates derived from
R-amino acids, stereoselective reduction of the resulting enones to allylic alcohols, and syn
epoxidation of the latter lead to enantiomerically pure 1-amino-2-hydroxy-3,4-epoxybutanes, key
intermediates in the synthesis. Reductive cleavage of the epoxy alcohols with Red-Al proceeds in
a highly regioselective way, giving 1-amino-2,4-dihydroxybutanes, from which diamino alcohol
hydroxyethylene isosteres are obtained by selective protection of the secondary 2-hydroxy group,
via cyclization to 1,3-oxazolidinone, and further elaboration of the 4-hydroxy. Both C-2 epimers of
1,4-diamino-2-hydroxybutanes are accessible by appropriate choice of the conditions for cyclization.
The approach is demonstrated by the synthesis of a series of six hydroxyethylene dipeptide isosteres,
including the diamino alcohol core of potent HIV-protease inhibitor ritonavir 18 and its C-2 epimer
11a
Small hydroxyethylene-based peptidomimetics inhibiting both HIV-1 and C. albicans aspartic protease
No full textWe have extended a highly flexible method for rapidly assembling aspartic protease inhibitors to produce symmetric and
asymmetric monohydroxyethylene peptidomimetics. This method is based on the prior synthesis of the central non-cleavable peptide-
bond isostere [NH2–P1cP10–NH2; c=hydroxyethylene isostere, HNCH(Bz)CHOHCH2CH(Bz)NH], with the possibility of
accurately controlling its stereochemistry (S,S,S or S,R,S), and subsequently adding appropriate flanking units, chosen from commercially
available amino acids, aromatic carboxylic acids, or phenoxyacetic acid (Poa) derivatives. The method was used to make
asymmetric inhibitors of general formula Kyn-Xaa-PhecPhe-dmPoa, (Kyn=kynurenic acid, Xaa=Val, Thr or d-thienylglycine,
Mr=716–754) and symmetric inhibitors of formula xPoa-PhecPhe-xPoa (xPoa=Poa or dimethyl-, hydroxy-, formyl- or acetyl-
Poa, Mr=553–609), with logPo/w values ranging from 4.1 to 7.6. Inhibition of HIV-PR did not depend on the stereochemistry of
the hydroxyl group, while it depended markedly on the substituents present on the Poa residues, with dmPoa being preferred over
Poa or its more hydrophilic derivatives. Conversely, inhibition of Candida albicans Sap2 was higher for the S,S,S epimers, and Poa
or its hydrophilic derivatives were preferred over dmPoa
A Catalytic Antibody Programmed for Torsional Activation of Amide Bond Hydrolysis
No full textAmidase antibody 312d6, obtained
against the sulfonamide hapten
4a that mimics the transition state for
hydrolysis of a distorted amide, accelerates
the hydrolysis of the corresponding
amides 1a ± 3a by a factor of 103 at pH 8.
The mechanisms of both the uncatalyzed
and antibody-catalyzed reactions were
studied. Between pH 8 and 12 the uncatalyzed
hydrolysis of N-toluoylindoles
1a and 3a shows a simple first-order
dependence on [OH], while hydrolysis
of 3a is zeroth-order in [OH] below
pH 8. The pH profile for hydrolysis of
the corresponding tryptophan amide 2a
is more complex due to the dissociation
of the zwitterion into an anion with
pKa 9.74; hydrolysis of the zwitterionic
and the anionic form of 2a both show
simple first-order dependence on
[OH]. Absence of 18O exchange between
H2
18O/18OH and the substrate, a
normal SKIE for both 1a (kH/kD1.12)
and 3a (kH/kD1.24) and the value of
the Hammett constant for hydrolysis
of p-substituted amides 3a ± e are consistent
with an ester-like mechanism in
which formation of the tetrahedral intermediate
is rate-determining and the
amine departs as anion. The 312d6-
catalyzed hydrolysis of 3a was studied
between pH 7.5 and 9, and its independence
of pH in this range indicates that
water is the reacting nucleophile. Hydrolysis
of 3a is only partially inhibited
by the sulfonamide hapten, and this
indicates that non-specific catalysis by
the protein accompanies the specific
process. Only the nonspecific process is
observed in the hydrolysis of amides 3
with para substituents other than methyl.
Binding studies on the corresponding
series of p-substituted sulfonamides
5a ± e confirm the high specificity of
antibody 312d6 for p-methyl substituted
substrates
Flexible synthesis of symmetric and non-symmetric hiv-1 protease inhibitors based on all-s-diaminodiol isosteres
No full textC2 symmetric and non-symmetric pseudopeptide inhibitors of HIV-1 protease, containing a S,S,S,S-diaminodiol isostere have been obtained by a synthetic strategy designed to couple a high degree of stereochemical control with complete flexibility in the choice of residues in the central core and flanking chains. Using this approach, inhibitors with IC50 values in the low nanomolar range were assembled from readily available aminoacids and carboxylic acids, chosen with the aid of molecular modelling
Synthesis of 6-deoxy-6-chloro and 6-deoxy-6-bromo derivatives of scleroglucan as intermediates for conjugation with methotrexate and other carboxylate containing compounds
No full textPolysaccharides are widely used as carriers in the field of drug delivery. We present a methodology to obtain water soluble drug-conjugates based on scleroglucan. Selective C-6 halogenation gives access to C-6 esters; conjugates between methotrexate and scleroglucan are described, potentially useful for antitumour therapy or in rheumatoid arthritis treatment
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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