Total Synthesis and Biological Evaluation of Pacidamycin D and Its 3′-Hydroxy Analogue

Full details of the total synthesis of pacidamycin D (<b>4</b>) and its 3′-hydroxy analogue <b>32</b> are described. The chemically labile <i>Z</i>-oxyacyl enamide moiety is the most challenging chemical structure found in uridylpeptide natural products. Key elements of our approach to the synthesis of <b>4</b> include the efficient and stereocontrolled construction of the <i>Z</i>-oxyvinyl halides <b>6</b> and <b>7</b> and their copper-catalyzed cross-coupling with the tetrapeptide carboxamide <b>5</b>, a thermally unstable compound containing a number of potentially reactive functional groups. This synthetic route also allowed us to easily prepare 3′-hydroxy analogue <b>32</b>. The assemblage by cross-coupling of the <i>Z</i>-oxyvinyl halide <b>6</b> and the carboxamide <b>5</b> at a late stage of the synthesis provided ready access to a range of uridylpeptide antibiotics and their analogues, despite their inherent labile nature with potential epimerization, simply by altering the tetrapeptide moiety

Expansion of Antibacterial Spectrum of Muraymycins toward <i>Pseudomonas aeruginosa</i>

It is urgent to develop novel anti-Pseudomonas agents that should also be active against multidrug resistant <i>P. aeruginosa</i>. Expanding the antibacterial spectrum of muraymycins toward <i>P. aeruginosa</i> was investigated by the systematic structure–activity relationship study. It was revealed that two functional groups, a lipophilic side chain and a guanidino group, at the accessory moiety of muraymycins were important for the anti-Pseudomonas activity, and analogue <b>29</b> exhibited antibacterial activity against a range of <i>P. aeruginosa</i> strains with the minimum inhibitory concentration values of 4–8 μg/mL

Conformational Restriction Approach to β‑Secretase (BACE1) Inhibitors: Effect of a Cyclopropane Ring To Induce an Alternative Binding Mode

Improvement of a drug’s binding activity using the conformational restriction approach with sp³ hybridized carbon is becoming a key strategy in drug discovery. We applied this approach to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds in which the ethylene linker of a known amidine-type inhibitor <b>2</b> was replaced with chiral cyclopropane rings. The synthesis and biologic evaluation of these compounds revealed that the <i>cis</i>-(1<i>S</i>,2<i>R</i>) isomer <b>6</b> exhibited the most potent BACE1 inhibitory activity among them. X-ray structure analysis of the complex of <b>6</b> and BACE1 revealed that its unique binding mode is due to the apparent CH−π interaction between the rigid cyclopropane ring and the Tyr71 side chain. A derivatization study using <b>6</b> as a lead molecule led to the development of highly potent inhibitors in which the structure–activity relationship as well as the binding mode of the compounds clearly differ from those of known amidine-type inhibitors