7 research outputs found
Total Synthesis of Ustiloxin D Utilizing an Ammonia–Ugi Reaction
Total synthesis of the highly functionalized
cyclic peptide natural
product, ustiloxin D, has been achieved in a convergent manner. Our
strategy incorporates an asymmetric allylic alkylation to construct
the <i>tert</i>-alkyl aryl ether linkage between the dopa
and isoleucine residues. The elaborated β-hydroxydopa derivative
is rapidly converted to a linear tripeptide through an ammonia–Ugi
reaction. Subsequent cyclization and global deprotection affords ustiloxin
D in six steps from a known β-hydroxydopa derivative
A General Method for Interconversion of Boronic Acid Protecting Groups: Trifluoroborates as Common Intermediates
We
have developed a general protocol for the interconversion of
diverse protected boronic acids, via intermediate organotrifluoroborates. <i>N</i>-Methyliminodiacetyl boronates, which have been hitherto
resistant to direct conversion to trifluoroborates, have been shown
to undergo fluorolysis at elevated temperatures. Subsequent solvolysis
of organotrifluoroborates in the presence of trimethylsilyl chloride
and a wide range of bis-nucleophiles enables the generation of a variety
of protected boronic acids
Total Synthesis of Mycocyclosin
The first total synthesis of mycocyclosin, a diketopiperazine natural product isolated from <i>M. tuberculosis</i>, is described. While direct oxidative coupling of tyrosine phenolic groups was unsuccessful, construction of the highly strained bicyclic framework was successfully accomplished through an intramolecular Miyaura–Suzuki cross-coupling to generate the biaryl linkage
Novel Conjugated Quinoline–Indoles Compromise Plasmodium falciparum Mitochondrial Function and Show Promising Antimalarial Activity
A novel
class of antimalarial compounds, based on an indol-3-yl
linked to the 2-position of a 4-aminoquinoline moiety, shows promising
activity against the malaria parasite, Plasmodium falciparum. Compounds with a quaternary nitrogen on the quinoline show improved
activity against the chloroquine-resistant K1 strain. Nonquaternerized
4-aminoquinolines retain significant potency but are relatively less
active against the K1 strain. Alkylation of the 4-amino group preferentially
improves the activity against the chloroquine-sensitive 3D7 strain.
The quinoline-indoles show only weak activity as inhibitors of β-hematin
formation, and their activities are only weakly antagonized by a hemoglobinase
inhibitor. The compounds appear to dissipate mitochondrial potential
as an early event in their antimalarial action and therefore may exert
their activity by compromising Plasmodium mitochondrial function. Interestingly, we observed a structural
relationship between our compounds and the anticancer and anthelminthic
compound, pyrvinium pamoate, which has also been proposed to exert
its action via compromising mitochondrial function
Characterization and Identification of Dityrosine Cross-Linked Peptides Using Tandem Mass Spectrometry
The use of mass spectrometry
coupled with chemical cross-linking
of proteins has become a powerful tool for proteins structure and
interactions studies. Unlike structural analysis of proteins using
chemical reagents specific for lysine or cysteine residues, identification
of gas-phase fragmentation patterns of endogenous dityrosine cross-linked
peptides have not been investigated. Dityrosine cross-linking in proteins
and peptides are clinical markers of oxidative stress, aging, and
neurodegenerative diseases including Alzheimer’s disease and
Parkinson’s disease. In this study, we investigated and characterized
the fragmentation pattern of a synthetically prepared dityrosine cross-linked
dimer of Aβ(1–16) using ESI tandem mass spectrometry.
We then detailed the fragmentation pattern of dityrosine cross-linked
Aβ(1–16), using collision induced dissociation (CID),
higher-energy collision induced dissociation (HCD), electron transfer
dissociation (ETD), and electron capture dissociation (ECD). Application
of these generic fragmentation rules of dityrosine cross-linked peptides
allowed for the identification of dityrosine cross-links in peptides
of Aβ and α-synuclein generated in vitro by enzymatic
peroxidation. We report, for the first time, the dityrosine cross-linked
residues in human hemoglobin and α-synuclein under oxidative
conditions. Together these tools open up the potential for automated
analysis of this naturally occurring post-translation modification
in neurodegenerative diseases as well as other pathological conditions
Optimization of 2‑Anilino 4‑Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity
Novel
antimalarial therapeutics that target multiple stages of
the parasite lifecycle are urgently required to tackle the emerging
problem of resistance with current drugs. Here, we describe the optimization
of the 2-anilino quinazoline class as antimalarial agents. The class,
identified from publicly available antimalarial screening data, was
optimized to generate lead compounds that possess potent antimalarial
activity against <i>P. falciparum</i> parasites comparable
to the known antimalarials, chloroquine and mefloquine. During the
optimization process, we defined the functionality necessary for activity
and improved <i>in vitro</i> metabolism and solubility.
The resultant lead compounds possess potent activity against a multidrug
resistant strain of <i>P. falciparum</i> and arrest parasites
at the ring phase of the asexual stage and also gametocytogensis.
Finally, we show that the lead compounds are orally efficacious in
a 4 day murine model of malaria disease burden
Optimization of 2‑Anilino 4‑Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity
Novel
antimalarial therapeutics that target multiple stages of
the parasite lifecycle are urgently required to tackle the emerging
problem of resistance with current drugs. Here, we describe the optimization
of the 2-anilino quinazoline class as antimalarial agents. The class,
identified from publicly available antimalarial screening data, was
optimized to generate lead compounds that possess potent antimalarial
activity against <i>P. falciparum</i> parasites comparable
to the known antimalarials, chloroquine and mefloquine. During the
optimization process, we defined the functionality necessary for activity
and improved <i>in vitro</i> metabolism and solubility.
The resultant lead compounds possess potent activity against a multidrug
resistant strain of <i>P. falciparum</i> and arrest parasites
at the ring phase of the asexual stage and also gametocytogensis.
Finally, we show that the lead compounds are orally efficacious in
a 4 day murine model of malaria disease burden