Bioorganic & Medicinal Chemistry Letters最新文献

The papain-like protease (PLpro) is a highly conserved domain encoded by the coronavirus (CoV) genome and it plays an essential role in the replication and maturation of the virus in addition to weakening host immune response. Due to the virus's reliance on PLpro for survival and propagation, small-molecule inhibitors of PLpro serve as an attractive model for direct-acting antiviral therapeutic agents against SARS-CoV-2. Building upon existing work aimed at designing covalent inhibitors against PLpro, we report the synthesis and structure-activity relationship of analogs based on the known covalent inhibitor 1 (Sanders, et al.2023). To evaluate the efficacy of synthesized derivatives, we conducted enzymatic inhibition assays, SARS-CoV-2/HeLa-ACE2 cellular potency and toxicity assays, and profiled the most promising analogs via in vitro ADME and in vivo pharmacokinetic studies. Additionally, we describe computational docking of profiled compounds bound to PLpro to elucidate the structure-activity relationship of compounds based on 1 and offer suggestions for optimizing the potency and selectivity of the electrophilic warhead and improving ADME and PK properties for this chemotype. Relative to the parent compound, new designs demonstrate comparable potency and target selectivity for PLpro. The accomplished SAR campaign provides novel insight for future development of antivirals against SARS-CoV-2.

Seeking new drug candidates among compounds of natural origin is an effective and widely used method of fighting various diseases, especially cancer. Lasalocid acid is one of the naturally occurring polyether ionophore antibiotics, which also exhibits interesting anticancer activity. Therefore, to expand the knowledge about the anticancer properties of lasalocid derivatives, a series of its new amides were synthesized and their antiproliferative activity against cancer cell lines was studied. Amides 7-9 with an aromatic substituent, displayed potent antiproliferative activity (IC₅₀: 0.84-5.18 μM) and demonstrated a good selectivity index (SI: 1.4-15.3). Furthermore, almost all of lasalocid amides overcame the drug resistance of the doxorubicin-resistant cancer cell line (LoVo/DX). Because the biological activity of ionophores is strictly connected with their ability to transport the Na⁺ cation through lipid bilayers, the crystal structure of the complex of compound 8 with the Na⁺ cation was resolved. Lasalocid amides exhibit a pseudocyclic structure and are able to coordinate the Na⁺ cation.

The discovery of novel anticancer agents remains a critical goal in medicinal chemistry, with innovative synthetic methodologies playing a pivotal role in advancing this field. Recent breakthroughs in CH activation reactions, cyclization reactions, multicomponent reactions, cross-coupling reactions, and photo- and electro-catalytic reactions have enabled the efficient synthesis of new molecular scaffolds exhibiting potent biological activities, including anticancer properties. These methodologies have facilitated the functionalization of natural products, the modification of bioactive molecules, and the generation of entirely new compounds, many of which demonstrate strong antitumor activity. This review summarizes the latest synthetic strategies employed over the past five years for discovering anticancer agents, focusing on their influence on drug design. Additionally, the role of new chemical reactions in expanding chemical space and overcoming challenges, such as drug resistance and selectivity, is highlighted, further emphasizing the importance of discovering novel reactions as a key trend in future drug development.

Prostaglandin E₂ receptor type 4 (EP4) agonists have been shown to be effective in treating experimental ulcerative colitis (UC) in animals and in human clinical trials, but their development has been impeded by unacceptable systemic side effects. In this study, a series of methylene phosphate prodrugs of a highly potent and selective prostaglandin EP4 receptor agonist were designed to target and remain localized in the gastrointestinal (GI) tract after either oral or rectal instillation. The prodrugs were designed to be converted to liberate active EP4 agonist by intestinal alkaline phosphate (IAP), a ubiquitous enzyme found at the luminal of the intestinal wall thus exposing the colon epithelial barrier while reducing systemic exposure to the active agonist. The prodrugs were shown to hydrolyze in plasma and after contact with GI tissue slices from ileum and colon. When optimized prodrugs were dosed orally, systemic peak exposure to the active agonist was not reduced, presumably due to IAP activity in the duodenum and small intestine. However, when dosed rectally, the prodrugs gave much reduced levels of EP4 agonist in the blood. An optimized prodrug was shown to be retained in the colon, when compared with free agonist after rectal administration in healthy mice and to be efficacious in a model of UC (the DSS mouse model). Plasma exposure to the active agonist was also much reduced in the mouse model of UC after 4 days of rectal dosing but after 7 days, one DSS mouse showed elevated systemic levels of the free agonist in the blood. The concept of efficacy and intestinal retention of an EP4 agonist-methylene phosphate prodrug was proven for rectal instillation but in DSS treated mice, severe disease appears to compromise the epithelia barrier sufficiently to allow some absorption of the prodrug to occur. Thus, further optimization of these prodrugs is required before a candidate can be selected for development for treating severe ulcerative colitis.

The pyrrolobenzodiazepines (PBDs) represent a major class of sequence-selective DNA-alkylating molecules, one example of which, in its dimeric DNA-cross-linking form, is employed as the payload in the anticancer Antibody Drug Conjugate (ADC) loncastuximab tesirine-lpyl. To date, PBD analogues have been produced with substituents at every position of the tricyclic skeleton except the C1-position. We report here the first synthesis of a C1-subsitituted PBD monomer and dimer, both of which possess DNA-binding activity and cytotoxicity in a cancer cell line.

Novel lipophilic cationic derivatives including quaternary ammonium salt and triphenylphosphine series were designed and synthesized using diosgenin (1) and sarsasapogenin (2) as substrates to improve the cytotoxicity and selectivity. Most of the derivatives showed higher cytotoxicity against all cancer cell lines tested, compound 13 exhibited the most superior activity against A549 cells with an IC₅₀ value of 0.95 μM, which was 34-fold of diosgenin. Preliminary cellular mechanism studies elucidated that compound 13 might arrest cell cycle at G0/G1 phase, trigger apoptosis via up-regulating the expression of Bax, down-regulating the expression of Bcl-2 and caspase-3, and induce an increase in the generation of intracellular reactive oxygen species (ROS) in A549 cells. In addition, molecular docking analysis revealed that compound 13 could occupy the active site of p38α-MAPK well and interact to the surrounding amino acids by salt bridge and conjugation. These results suggested that compound 13 had the potential to serve as an antitumor lead agent, probably exert antitumor effect through mitochondrial pathway and p38α MAPK pathway.

Cryptosporidium parvum is a protozoan parasite that causes severe diarrheal illness in children and each year nearly 50,000 children under age 5 die due to the disease. Despite tremendous research efforts, there remains a lack of effective therapies and vaccines. Novel inhibitors against N-myristoyltransferase of C. parvum (CpNMT) are potential starting points towards the development of effective therapies. In quest of promising selective CpNMT inhibitors, structure guided modifications of compound 1 (2-chloro-5-(ethyl-phenyl-sulfamoyl)-N-[2-(2-oxo-pyrrolidin-1-yl)-phenyl]-benzamide) were performed. The resulting compounds were evaluated for selective inhibition of CpNMT over the host enzyme HsNMT1. Compounds 11e and 11f exhibited good inhibition, with IC₅₀ values of 2.5 and 2.8 μM, respectively. While 11e was slightly more selective towards CpNMT over HsNMT1 (∼5-fold), compound 11f showed >40-fold selectivity, validating our structure-based design approaches. Compounds 11e and 11f were also found to be efficacious against C. parvum growth, with EC₅₀ values of 6.9 and 16.4 μM, respectively.

A novel and new type of tetracycline with a different mechanism of action was necessary, due to the drug resistance of existing tetracyclines. This study outlines the synthesis and antibacterial evaluation of anhydro-tetracycline derivatives, which are unconventional tetracyclines with unique mechanisms of action. These derivatives include C4-NH₂, C4-OH, and C9-substituted variations, and our synthetic approach focuses on semi-synthesis using natural tetracyclines as the starting precursors. Several derivatives of C4-NH₂, C4-OH, and C9-substituted compounds have demonstrated effective antibiotic activity against both Gram-positive and Gram-negative bacteria.

In a previous study, we reported that nilotinib, a BCR-ABL tyrosine kinase inhibitor, possesses moderate antimalarial activity against PfK1 and PfFCR3. As a part of our efforts to develop novel antimalarial agents, a series of novel triazine analogs was identified as potent antimalarial agents via structure modification of nilotinib. Compound 15a showed strong antimalarial activities against PfK1 and PfFCR3 with IC₅₀ values of 0.28 and 0.29 µM, respectively.

FL118, a camptothecin derivative with dual mechanisms of action through topoisomerase I inhibition and proteasome-mediated degradation of anti-apoptotic proteins exhibits potent anti-tumor activity while remaining resistant to drug efflux transporters. This work describes the targeted delivery of FL118 to tumors via antibody-drug conjugates (ADCs) using the pH-sensitive CL2A linker. ADCs targeting Trop2, HER2, and EGFR exhibited potent in vitro cytotoxicity, with IC₅₀ values as low as 0.025 nM in Trop2-positive FaDu cells. In vivo, Sac-CL2A-FL118 showed 130 % tumor growth inhibition (TGI) at 7 mg/kg in Trop2-expressing xenografts surpassing Trodelvy®. Pharmacokinetic evaluations revealed that FL118-ADCs exhibited a 2.6-fold increase in AUC and approximately 1.7-fold higher C_max compared to Trodelvy®, confirming their favorable profiles and supporting their potential as a promising therapeutic approach.