ACS Medicinal Chemistry Letters最新文献

Rhomboid proteases play a variety of physiological roles, but rhomboid protease inhibitors have been mostly developed for the E. coli model rhomboid GlpG. In this work, we screened different electrophilic scaffolds against the human mitochondrial rhomboid PARL and found 4-oxo-β-lactams as submicromolar inhibitors. Multifaceted computations suggest explanations for the activity at the molecular scale and provide models of covalently bound complexes. Together with the straightforward synthesis of the 4-oxo-β-lactam scaffold, this may pave the way toward selective, nonpeptidic PARL inhibitors.

Rhomboid proteases play a variety of physiological roles, but rhomboid protease inhibitors have been mostly developed for the E. coli model rhomboid GlpG. In this work, we screened different electrophilic scaffolds against the human mitochondrial rhomboid PARL and found 4-oxo-β-lactams as submicromolar inhibitors. Multifaceted computations suggest explanations for the activity at the molecular scale and provide models of covalently bound complexes. Together with the straightforward synthesis of the 4-oxo-β-lactam scaffold, this may pave the way toward selective, nonpeptidic PARL inhibitors.

The cochlearols and ganocochlearins are natural products with unique antifibrotic and renoprotective activities in models of kidney disease. They represent compelling lead compounds for pharmacological intervention against kidney disease, often characterized by renal fibrosis. We report a four-step synthesis of (±)-cochlearol T (1) and the first reported syntheses of (±)-ganocochlearin A (2) and (±)-cochlearol Y (3) through a strategy that includes a Robinson annulation and unexpected oxidative aromatization. We also access tricyclic intermediate 12 that represents a formal synthesis of ganocins A-C and ganocochlearins C-D. We investigated the activity of these synthesized compounds in vitro by inducing fibrosis in a human kidney cell line with TGF-β1. The effect on fibrosis was assessed by qPCR and Western blot studies. We detected significantly lower mRNA gene and protein expression of fibrosis markers for all three natural products.

The cochlearols and ganocochlearins are natural products with unique antifibrotic and renoprotective activities in models of kidney disease. They represent compelling lead compounds for pharmacological intervention against kidney disease, often characterized by renal fibrosis. We report a four-step synthesis of (±)-cochlearol T (1) and the first reported syntheses of (±)-ganocochlearin A (2) and (±)-cochlearol Y (3) through a strategy that includes a Robinson annulation and unexpected oxidative aromatization. We also access tricyclic intermediate 12 that represents a formal synthesis of ganocins A–C and ganocochlearins C–D. We investigated the activity of these synthesized compounds in vitro by inducing fibrosis in a human kidney cell line with TGF-β1. The effect on fibrosis was assessed by qPCR and Western blot studies. We detected significantly lower mRNA gene and protein expression of fibrosis markers for all three natural products.

Several antiepileptic drugs (AEDs) have been found to inhibit human carbonic anhydrases (hCAs), paving the way for repurposing AEDs for the treatment of various diseases, including cancer. Here, the hCAs inhibitory effects of levetiracetam, a highly prescribed AED that does not bear a common zinc-binding group, were investigated in vitro and in silico. Levetiracetam inhibited all tested hCAs, although with a specific profile compared to the reference acetazolamide, with remarkable efficacy against tumor-associated hCA IX and XII. Molecular docking and dynamics (MD) simulations emphasized H-bonding to the Zn(II)-coordinated water as a major anchor point for hCAs, as well as a persistent interaction within the catalytic site of hCA isoforms IX and XII compared to II, which correlates with experimental data. Our results may explain why levetiracetam is also clinically effective as an antitumor agent in patients developing epilepsy as a consequence of brain tumors.

Psychedelic compounds, particularly psilocybin and psilocin, have shown significant therapeutic potential in treating neurological and psychiatric disorders. However, their bioavailability, rapid metabolism, and stability challenges have limited their clinical use. This Patent Highlight reviews recent innovations in psychedelic drug delivery systems and the development of psilocin analogs aimed at improving their pharmacokinetic and pharmacodynamic profiles. Three patents─focused on controlled-release delivery systems, ester analogs, and acetal/ketal derivatives─present novel approaches to enhancing the stability, bioavailability, and efficacy of psilocin and related compounds. These advancements promise more effective treatments for conditions such as depression, chronic pain, and neurodegenerative diseases.

The rapid advances in cancer research have led to novel therapeutic approaches focusing on previously undruggable targets and immune evasion mechanisms. Recent innovations exemplify these cutting-edge strategies, particularly in KRAS-targeting therapies using PROTAC technology and immune modulation to address resistance in cancer cells. These developments present promising methods for degrading oncogenic proteins and enhancing immune system responses, potentially transforming the cancer treatment landscape. This Patent Highlight showcases these breakthroughs, emphasizing their significant potential to transform cancer therapy.

This research investigates boronated tryptophans as potential boron delivery agents for boron neutron capture therapy (BNCT) of cancer. We synthesized both enantiomers of 5- and 6-boronotryptophans (1a and 1b) using simple and inexpensive methods. Their uptake was assessed in two human cancer cell lines, CAL27 (head and neck cancer) and U87-MG (brain cancer), and compared to l-p-boronophenylalanine (l-BPA) as a reference. To determine whether these tryptophan derivatives are substrates for large amino acid transporter 1, we performed molecular dynamics simulations to explore their transport mechanism. Our findings reveal differences in boron compound accumulation between the cancer cell lines, indicating that tryptophan derivatives could serve as effective boron carriers when the clinically used boron carrier, BPA, is ineffective.

Recent advancements in cancer therapy have led to groundbreaking approaches targeting critical oncogenic pathways. This Patent Highlight explores four essential patents that focus on modulating ligand-receptor interactions from placental immunology, degrading RAF proteins with MEK1/2 degraders, and employing PROTAC technology to degrade Cyclin D, CDK4, and CDK6 proteins. These innovations aim to overcome traditional therapy limitations and address resistance in cancers such as breast, lung, and RAS-altered cancers. This publication examines these inventions' mechanisms, findings, and implications in modern cancer treatment.

Recent innovations in psychedelic research have led to the development of novel compounds designed to enhance the therapeutic potential of psilocin and related tryptamines. This Patent Highlight reviews three essential patents that focus on improving the stability, bioavailability, and efficacy of these compounds for treating mental health disorders such as depression, anxiety, and substance use disorders. The compounds-4-pivaloyloxy-N-methyltryptammonium chloride, alkyl quaternary ammonium tryptamines, and 4-pivaloyloxy-N-methyltryptammonium derivatives-represent significant advancements in the field of psychedelic-assisted therapy. These innovations offer new hope for more reliable and effective treatments, particularly in addressing the limitations associated with traditional psychedelics. The findings from preclinical studies support the potential of these compounds to play a vital role in the treatment of mental and neurological disorders.