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