Synthesis and Structural Optimization of ATG4B Inhibitors for the Attenuation of Autophagy in Glioblastoma.

Glioblastoma, a prevalent malignant CNS tumor, presents a therapeutic challenge because of resistance to standard treatments, including radiation therapy and temozolomide. Both modalities induce autophagy, thereby paradoxically promoting tumor survival. The cysteine protease ATG4B is implicated in this cellular process, which highlights the enzyme as a viable therapeutic target for glioblastoma. We have developed streamlined syntheses for ATG4B inhibitor NSC185058, its derivatives, and fluorogenic ATG4B substrate pim-FG-PABA-AMC. We leveraged these findings to rapidly identify novel compound MJO445, which demonstrates markedly greater potency biochemically and in cells.

NU-1223, a simplified analog of alstonine, with 5-HT2cR agonist-like activity, rescues memory deficit and positive and negative symptoms in subchronic phencyclidine mouse model of schizophrenia.

The serotonin (5-HT)2 C receptor(R) is a widely distributed G-protein-coupled receptor, expressed abundantly in the central nervous system. Alstonine is a natural product that has significant properties of atypical antipsychotic drugs (AAPDs), in part attributed to 5-HT2 CR agonism. Based on alstonine, we developed NU-1223, a simplified ß carboline analog of alstonine, which shows efficacies comparable to alstonine and to other 5-HT2 CR agonists, Ro-60-0175 and lorcaserin. The 5-HT2 CR antagonism of some APDs, including olanzapine, contributes to weight gain, a major side effect which limits its tolerability, while the 5-HT2 CR agonists and/or modulators, may minimize weight gain. We used the well-established rodent subchronic phencyclidine (PCP) model to test the efficacy of NU-1223 on episodic memory, using novel object recognition (NOR) task, positive (locomotor activity), and negative symptoms (social interaction) of schizophrenia (SCH). We found that NU-1223 produced both transient and prolonged rescue of the subchronic PCP-induced deficits in NOR and SI. Further, NU-1223, but not Ro-60-0175, blocked PCP and amphetamine (AMPH)-induced increase in LMA in subchronic PCP mice. These transient efficacies in LMA were blocked by the 5-HT2 CR antagonist, SB242084. Sub-chronic NU-1223 treatment rescued NOR and SI deficits in subchronic PCP mice for at least 39 days after 3 days injection. Chronic treatment with NU-1223, ip, twice a day for 21 days, did not increase average body weight vs olanzapine. These findings clearly indicate NU-1223 as a class of small molecules with a possible 5-HT2 CR-agonist-like mechanism of action, attributing to its efficacy. Additional in-depth receptor mechanistic studies are warranted, as this small molecule, both transiently and chronically rescued PCP-induced deficits. Furthermore, NU-1223 did not induce weight gain post long-term administrations vs AAPDs such as olanzapine, making NU-1223 a putative therapeutic compound for SCH.

Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors.

The mitogen-activated protein kinase signaling cascade is conserved across eukaryotes, where it plays a critical role in the regulation of activities including proliferation, differentiation, and stress responses. This pathway propagates external stimuli through a series of phosphorylation events, which allows external signals to influence metabolic and transcriptional activities. Within the cascade, MEK, or MAP2K, enzymes occupy a molecular crossroads immediately upstream to significant signal divergence and cross-talk. One such kinase, MAP2K7, also known as MEK7 and MKK7, is a protein of great interest in the molecular pathophysiology underlying pediatric T cell acute lymphoblastic leukemia (T-ALL). Herein, we describe the rational design, synthesis, evaluation, and optimization of a novel class of irreversible MAP2K7 inhibitors. With a streamlined one-pot synthesis, favorable in vitro potency and selectivity, and promising cellular activity, this novel class of compounds wields promise as a powerful tool in the study of pediatric T-ALL.

Discovery of Highly Potent Serotonin 5-HT2 Receptor Agonists Inspired by Heteroyohimbine Natural Products.

The serotonin 5-HT2 receptors are important pharmaceutical targets involved in signaling pathways underlying various neurological, psychiatric, and cardiac functions and dysfunctions. As such, numerous ligands for the investigation of these receptors' activity and downstream effects have been developed synthetically or discovered in nature. For example, the heteroyohimbine natural product alstonine exhibits antispychotic activity mediated by 5-HT2A/2C agonism. In this work, we identified a heteroyohimbine metabolite containing a serotonin pharmacophore and truncated the scaffold, leading to the discovery of potent agonist activity of substituted tetrahydro-ß-carbolines across the 5-HT2 receptor family. Extensive SAR development resulted in compound 106 with EC50 values of 1.7, 0.58, and 0.50 nM at 5-HT2A, 5-HT2B, and 5-HT2C, respectively. Docking studies suggest a π-stacking interaction between the tetrahydro-ß-carboline core and conserved residue Trp6.48 as the structural basis for this activity. This work lays a foundation for future investigation of these compounds in neurological and psychiatric disorders.

Acid-Promoted Cascade Reaction of N-(4-Chloroquinolin-3-yl)carbamates with Amines: One-Pot Assembly of Imidazo[4,5-c]quinolin-2-one.

An acid-promoted cascade reaction of 4-chloroquinolin-3-yl carbamates with amines is described. This method achieves the formation of two new C-N bonds through an intermolecular amination/intramolecular cyclization reaction sequence. In combination with subsequent Suzuki coupling, this three-component telescopic procedure provides rapid access to various bioactive imidazo[4,5-c]quinolin-2-one derivatives.

Efficient Synthesis of 1,9-Substituted Benzo[h][1,6]naphthyridin-2(1H)-ones and Evaluation of their Plasmodium falciparum Gametocytocidal Activities.

A novel three-component, two-step, one-pot nucleophilic aromatic substitution (SNAr)-intramolecular cyclization-Suzuki coupling reaction was developed for the synthesis of benzo[h][1,6]naphthyridin-2(1H)-ones (Torins). On the basis of the new efficiently convergent synthetic route, a library of Torin analogs was synthesized. The antimalarial activities of these compounds were evaluated against asexual parasites using a growth inhibition assay and gametocytes using a viability assay.