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[Display omitted] Development of selective or dual proteasome subunit inhibitors based on syringolin B as a scaffold is described. We focused our efforts on a structure–activity relationship study of inhibitors with various substituents at the 3-position of the macrolactam moiety of syringolin B analogue to evaluate whether this would be sufficient to confer subunit selectivity by using sets of analogues with hydrophobic, basic and acidic substituents, which were designed to target Met45, Glu53 and Arg45 embedded in the S1 subsite, respectively. The structure–activity relationship study using systematic analogues provided insight into the origin of the subunit-selective inhibitory activity. This strategy would be sufficient to confer subunit selectivity regarding β5 and β2 subunits. [ABSTRACT FROM AUTHOR]

Neuromedin U (NMU) are bioactivepeptides with a common C-terminalheptapeptide sequence (FLFRPRN-amide, 1a) among mammals,which is responsible for receptor activation, namely NMU receptortypes 1 (NMUR1) and 2 (NMUR2). Among the various physiological actionsof NMU, the anorexigenic effect has recently attracted attention indrug discovery efforts for treating obesity. Although several structure–activityrelationship (SAR) studies have been reported, receptor-selectivesmall peptide agonists have yet to be disclosed. Herein a SAR studyof 1a-derived peptide derivatives is described. We initiallyscreened both human NMUR1- and NMUR2-selective peptides in calcium-mobilizationassays with cells transiently expressing receptors. Then we performeda precise assay with a stable expression system of receptors and consequentlydiscovered hexapeptides 8dand 6bpossessingselective agonist activity toward each respective receptor. Hexapeptide 6b, which selectively activates NMUR2 without significantNMUR1 activation, should aid in the development of anorexigenic drugsas well as advance NMU-related endocrinological research. [ABSTRACT FROM AUTHOR]

Abstract: KPU-105 (4), a potent anti-microtubule agent that contains a benzophenone was derived from the diketopiperazine-type vascular disrupting agent (VDA) plinabulin 3, which displays colchicine-like tubulin depolymerization activity. To develop derivatives with more potent anti-microtubule and cytotoxic activities, we further modified the benzophenone moiety of 4. Accordingly, we obtained a 4-fluorobenzophenone derivative 16j that inhibited tumor cell growth in vitro with a subnanomolar IC50 value against HT-29 cells (IC50 =0.5nM). Next, the effect of 16j on mitotic spindles was evaluated in HeLa cells. Treatment with 3nM of 16j partially disrupted the interphase microtubule network. By contrast, treatment with the same concentration of CA-4 barely affected the microtubule network, indicating that 16j exhibited more potent anti-mitotic effects than did CA-4. [Copyright &y& Elsevier]