Porphyrin–Peptoid Conjugates: Face-to-Face Display of Porphyrins on Peptoid Helices

Distance, orientation, and number controlled porphyrin–peptoid conjugates (PPCs) were efficiently synthesized. Cofacial (<b>1</b>, <b>2</b>, and <b>4</b>), slipped-cofacial (<b>3</b>), and unstructured (<b>5</b>) arrangements of porphyrins provided distinct optical and electronic properties characterized by UV–vis and circular dichroism spectroscopy. In addition, ECCD spectra confirmed the handedness of peptoid helices

Synthesis of Fused Polycyclic 1,4-Benzodiazepines via Metal-Free Cascade [5 + 2]/[2 + 2] Cycloadditions

A metal-catalyst-free, mild, and efficient synthetic protocol for polycyclic 1,4-benzodiazepines via cascade [5 + 2]/[2 + 2] cycloadditions between pyridinium zwitterions and arynes is reported. Mechanistic experiments revealed that pyridinium zwitterions act as 1,5-dipoles in [5 + 2] cycloadditions with arynes for the construction of 1,4-benzodiazepines, which further undergo [2 + 2] cycloaddition resulting in the one-pot formation of one C–N bond and three C–C bonds

Synthesis of Fused Polycyclic 1,4-Benzodiazepines via Metal-Free Cascade [5 + 2]/[2 + 2] Cycloadditions

A metal-catalyst-free, mild, and efficient synthetic protocol for polycyclic 1,4-benzodiazepines via cascade [5 + 2]/[2 + 2] cycloadditions between pyridinium zwitterions and arynes is reported. Mechanistic experiments revealed that pyridinium zwitterions act as 1,5-dipoles in [5 + 2] cycloadditions with arynes for the construction of 1,4-benzodiazepines, which further undergo [2 + 2] cycloaddition resulting in the one-pot formation of one C–N bond and three C–C bonds

Mitochondria-Targeting Peptoids

Mitochondria-specific delivery methods offer a valuable tool for studying mitochondria-related diseases and provide breakthroughs in therapeutic development. Although several small-molecule and peptide-based transporters have been developed, peptoids, proteolysis-resistant peptidomimetics, are a promising alternative to current approaches. We designed a series of amphipathic peptoids and evaluated their cellular uptake and mitochondrial localization. Two peptoids with cyclohexyl residues demonstrated highly efficient cell penetration and mitochondrial localization without significant adverse effects on the cells and mitochondria. These mitochondria-targeting peptoids could facilitate the selective and robust targeted delivery of bioactive compounds, such as drugs, antioxidants, and photosensitizers, with minimal off-target effects

Discovery of an Orally Bioavailable Gonadotropin-Releasing Hormone Receptor Antagonist

We developed a compound library for orally available gonadotropin-releasing hormone (GnRH) receptor antagonists that were based on a uracil scaffold. On the basis of in vitro activity and CYP inhibition profile, we selected <b>18a</b> (SKI2496) for further in vivo studies. Compound <b>18a</b> exhibited more selective antagonistic activity toward the human GnRH receptors over the GnRHRs in monkeys and rats, and this compound also showed inhibitory effects on GnRH-mediated signaling pathways. Pharmacokinetic and pharmacodynamic evaluations of <b>18a</b> revealed improved bioavailability and superior gonadotropic suppression activity compared with Elagolix, the most clinically advanced compound. Considering that <b>18a</b> exhibited highly potent and selective antagonistic activity toward the <i>h</i>GnRHRs along with favorable pharmacokinetic profiles, we believe that <b>18a</b> may represent a promising candidate for an orally available hormonal therapy

Functional Imaging of Legumain in Cancer Using a New Quenched Activity-Based Probe

Legumain is a lysosomal cysteine protease whose biological function remains poorly defined. Legumain activity is up-regulated in most human cancers and inflammatory diseases most likely as the result of high expression in populations of activated macrophages. Within the tumor microenvironment, legumain activity is thought to promote tumorigenesis. To obtain a greater understanding of the role of legumain activity during cancer progression and inflammation, we developed an activity-based probe that becomes fluorescent only upon binding active legumain. This probe is highly selective for legumain, even in the context of whole cells and tissues, and is also a more effective label of legumain than previously reported probes. Here we present the synthesis and application of our probe to the analysis of legumain activity in primary macrophages and in two mouse models of cancer. We find that legumain activity is highly correlated with macrophage activation and furthermore that it is an ideal marker for primary tumor inflammation and early stage metastatic lesions

Discovery of an Orally Bioavailable Gonadotropin-Releasing Hormone Receptor Antagonist

We developed a compound library for orally available gonadotropin-releasing hormone (GnRH) receptor antagonists that were based on a uracil scaffold. On the basis of in vitro activity and CYP inhibition profile, we selected <b>18a</b> (SKI2496) for further in vivo studies. Compound <b>18a</b> exhibited more selective antagonistic activity toward the human GnRH receptors over the GnRHRs in monkeys and rats, and this compound also showed inhibitory effects on GnRH-mediated signaling pathways. Pharmacokinetic and pharmacodynamic evaluations of <b>18a</b> revealed improved bioavailability and superior gonadotropic suppression activity compared with Elagolix, the most clinically advanced compound. Considering that <b>18a</b> exhibited highly potent and selective antagonistic activity toward the <i>h</i>GnRHRs along with favorable pharmacokinetic profiles, we believe that <b>18a</b> may represent a promising candidate for an orally available hormonal therapy

Synthesis and Biological Evaluation of Aryloxazole Derivatives as Antimitotic and Vascular-Disrupting Agents for Cancer Therapy

A series of aryloxazole, thiazole, and isoxazole derivatives was synthesized as vascular-targeting anticancer agents. Antiproliferative activity and tumor vascular-disrupting activity of all of the synthesized compounds were tested in vitro using various human cancer cell lines and HUVECs (human umbilical vein endothelial cells). Several compounds with an arylpiperazinyl oxazole core showed excellent cytotoxicity and metabolic stability in vitro. Among this series, two representative compounds (<b>6</b>-<b>48</b> and <b>6</b>-<b>51</b>) were selected and tested for the evaluation of anticancer effects in vivo using tumor-bearing mice. Compound <b>6</b>-<b>48</b> effectively reduced tumor growth (42.3% reduction in size) at the dose of 100 mg/kg. We believe that compound <b>6</b>-<b>48</b> will serve as a good lead compound for antimitotic and vascular-disrupting agents; further investigation to improve the in vivo efficacy of this series is underway

Discovery of Leucyladenylate Sulfamates as Novel Leucyl-tRNA Synthetase (LRS)-Targeted Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitors

Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound <b>18</b> selectively inhibited LRS-mediated mTORC1 activation and exerted specific cytotoxicity against colon cancer cells with a hyperactive mTORC1, suggesting that <b>18</b> may offer a novel treatment option for human colorectal cancer

Discovery of Leucyladenylate Sulfamates as Novel Leucyl-tRNA Synthetase (LRS)-Targeted Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitors

Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound <b>18</b> selectively inhibited LRS-mediated mTORC1 activation and exerted specific cytotoxicity against colon cancer cells with a hyperactive mTORC1, suggesting that <b>18</b> may offer a novel treatment option for human colorectal cancer