Bioorganic & Medicinal Chemistry最新文献

Platinum-based anticancer drugs have been at the forefront of cancer chemotherapy, with cisplatin emerging as a pioneer in the treatment of various malignancies. This review article provides a comprehensive overview of the evolution of platinum-based anticancer therapeutics, focusing on the development of cisplatin, platinum(IV) prodrugs, and the integration of photodynamic therapy (PDT) for enhanced cancer treatment results. The first section of the review delves into the historical context and molecular mechanisms underlying the success of cisplatin, highlighting its DNA binding properties and subsequent interference with cellular processes. Despite its clinical efficacy, the inherent limitations, including dose-dependent toxicities and acquired resistance, accelerated the exploration of novel platinum derivatives. This led to the emergence of platinum(IV) prodrugs, designed to overcome resistance mechanisms and enhance selectivity through targeted drug delivery. The subsequent section provides an in-depth analysis of the principles of design and structural modifications employed in the development of platinum(IV) prodrugs. The transitions to the incorporation of photodynamic therapy (PDT) stands out as a synergistic approach to platinum-based anticancer treatment. The photophysical properties of platinum complexes are discussed in the context of their potential application in PDT, emphasizing on combined cytotoxic effects of platinum-based drugs and light-induced reactive oxygen species generation. This dual-action approach holds great promise for overcoming the limitations of traditional chemotherapy as well as producing superior therapeutic outcomes. Overall, the present report explores the latest developments in the development and use of platinum complexes, highlighting novel strategies such combination treatments, targeted delivery methods, and the generation of multifunctional complexes. It also provides a comprehensive overview of the current landscape while proposing future directions for the development of next-generation platinum-based anticancer therapeutics.

Dual orexin receptor antagonists (DORAs) are approved for the treatment of sleep onset and/or sleep maintenance insomnia. In the present disclosure, we report the discovery of a new class of DORAs designed to treat sleep disorders requiring a fast onset and a short duration of action (<4 h). We used early human pharmacokinetic-pharmacodynamic (PK-PD) predictions and in vivo experiments to identify DORAs eliciting this specific hypnotic profile. A high-throughput screening campaign revealed hits based on a rarely precedented tricyclic pyrazolidine scaffold. After unsuccessful structure–activity-relationship (SAR) studies on this hit series, a scaffold hopping exercise, aimed at reducing the molecular complexity of the tricyclic scaffold, resulted in the discovery of the 2-acyl-1-biarylmethylpyrazolidine series. SAR studies on this achiral series gave rise to the lead compound DORA 42. In vitro and in vivo parameters of DORA 42, and its PK-PD simulation for human use are detailed.

This study comprehensively explored the helix-stabilizing effects of amine-bearing hydrocarbon cross-links (ABXs), revealing their context-dependent nature influenced by various structural parameters. Notably, we identified a 9-atom ABX as a robust helix stabilizer, showcasing versatile synthetic adaptability while preserving peptide water solubility. Future investigations are imperative to fully exploit this system’s potential and enrich our chemical toolkit for designing innovative peptide-based biomolecules.

Tagging of cell permeable nuclear localization sequence (NLS) with receptor targeting peptide vectors is an attractive strategy for selectively targeted translocation of therapeutic cargoes. The present study aimed at grafting nuclear localization sequence (NLS) onto breast cancer targeting rL-A9 peptide. Molecular docking analysis revealed higher binding affinity of the peptide, DOTA-NLS-rL-A9 (−26.1 kJ/mol) towards HER2 receptor in comparison to DOTA-rL-A9 peptide (−22.2 kJ/mol). Confocal microscopy data suggested significantly enhanced cellular internalization of NLS-tagged peptide. The engineered HER2-selective, DOTA-NLS-rL-A9 peptide scaffold was radiolabeled with Lu-177 for intracellular delivery of the theranostic radionuclide into tumor cells. [¹⁷⁷Lu]Lu-DOTA-NLS-rL-A9 exhibited significantly enhanced binding affinity (4.58 ± 1.77 nM) towards human breast carcinoma SKBR3 cells and cellular internalization (85 % at 24 h) compared to its original analog, [¹⁷⁷Lu]Lu-DOTA-rL-A9. In vivo biodistribution studies showed consistent retention of [¹⁷⁷Lu]Lu-DOTA-NLS-rL-A9 in the tumor with negligible washout of radioactivity (∼4.1 % ID/g at 48 h). Prolonged tumor activity with rapid off-target tissue clearance resulted in significantly high tumor-to-background ratios. The radiopeptide, [¹⁷⁷Lu]Lu-DOTA-NLS-rL-A9 thus, being precisely confined into HER2-expressing tumor cells and exhibiting favourable pharmacokinetic features is an efficient candidate for further screening.

Triple-negative breast cancer (TNBC) stands out as the most formidable variant of breast cancer, predominantly affecting younger women and characterized by a bleak outlook and a high likelihood of spreading. The absence of safe and effective targeted treatments leaves standard cytotoxic chemotherapy as the primary option. The role of protein kinases, frequently altered in many cancers, is significant in the advancement and drug resistance of TNBC, making them a logical target for creating new, potent therapies against TNBC. Recently, an array of promising small molecules aimed at various kinases have been developed specifically for TNBC, with combination studies showing a synergistic improvement in combatting this condition. This review underscores the effectiveness of small molecule kinase inhibitors in battling the most lethal form of breast cancer and sheds light on prospective pathways for crafting novel treatments.

Berberine is a quaternary ammonium isoquinoline alkaloid derived from traditional Chinese medicines Coptis chinensis and Phellodendron chinense. It has many pharmacological activities such as hypoglycemic, hypolipidemic, anti-tumor, antimicrobial and anti-inflammatory. Through structural modifications at various sites of berberine, the introduction of different groups can change berberine’s physical and chemical properties, thereby improving the biological activity and clinical efficacy, and expanding the scope of application. This paper reviews the research progress and structure–activity relationships of berberine in recent years, aiming to provide valuable insights for the exploration of novel berberine derivatives.

The bromodomain-containing protein 4 (BRD4), which is a key epigenetic regulator in cancer, has emerged as an attractive target for the treatment of melanoma. In this study, we investigate 7-phenoxy-benzimidazole derivative 12, which is a novel BRD4 inhibitor for the treatment of melanoma, by performing scaffold hopping on the previously reported benzimidazole derivative 1. Despite their good oral and intravenous exposure, the compounds obtained by modifying derivate 1 exhibit mutagenicity, which was confirmed by the positive Ames test results. Based on our hypothesis that the cause of the Ames test positivity is the metabolic intermediates generated from those chemical series, we implemented a scaffold hopping strategy to avoid the N-benzyl moiety by relocating the substituent groups to preserve the essential interaction. Based on this strategy, we successfully obtained compound 12; the Ames test results of this compound were negative. Notably, compound 12 not only exhibited a favorable pharmacokinetic (PK) profile but also significant tumor growth inhibition in a mouse melanoma xenograft model, indicating its potential as a therapeutic agent for the treatment of melanoma.

JQ1 is a wonder therapeutic molecule that selectively inhibits the BRD4 signaling pathway and is thus widely used in the anticancer drug discovery program. Due to its unique selective BRD4 binding property, its applications are further extended in the design and synthesis of bi-functional PROTAC molecules. This BRD4 targeting PROTAC molecule selectively degrades the protein by proteolysis. There are several modifications of JQ1 known to date and extensively explored for their applications in PROTAC technology by several research groups in academia as well as industry for targeting oncogenic genes. In this review, we have covered the discovery and synthesis of the JQ1 molecule. The SAR of the JQ1 analogs will help researchers develop potent JQ1 compounds with improved inhibitory properties against malignant cells. Furthermore, we explored the potential application of JQ1 analogs in PROTAC technology. The brief history of the bromodomain family of proteins, as well as the obstacles connected with PROTAC technology, can help comprehend the context of the current research, which has the potential to improve the drug development process. Overall, this review comprehensively appraises JQ1 molecules and their prior implementation in PROTAC technology and cancer therapy.

Chemical RNA modification has emerged as a flexible approach for post-synthetic modifications in chemical biology research. Guide RNA (gRNA) plays a crucial role in the clustered regularly interspaced short palindromic repeats and associated protein system (CRISPR-Cas). Several toolkits have been developed to regulate gene expression and editing through modifications of gRNA. However, conditional regulation strategies to control gene editing in cells as required are still lacking. In this context, we introduce a strategy employing a cyclic disulfide-substituted acylating agent to randomly acylate the 2′-OH group on the gRNA strand. The CRISPR-Cas systems demonstrate off–on transformation activity driven by redox-triggered disulfide cleavage and undergo intramolecular cyclization, which releases the functionalized gRNA. Dithiothreitol (DTT) exhibits superior reductive capabilities in cleaving disulfides compared to glutathione (GSH), requiring fewer reductants. This acylation method with cyclic disulfides enables conditional control of CRISPR-Cas9, CRISPR-Cas13a, RNA hybridization, and aptamer folding. Our strategy facilitates precise in vivo control of gene editing, making it particularly valuable for targeted applications.

Gout is an autoinflammatory disorder characterized by the accumulation of monosodium urate crystals in joints and other tissues, representing the predominant type of inflammatory arthritis with a notable prevalence and propensity for severe outcomes. The NLRP3 inflammasome, a member of the pyrin domain-containing NOD-like receptor family, exerts a substantial impact on both innate and adaptive immune responses and serves as a pivotal factor in the pathogenesis of gout. In recent years, there has been significant academic and industrial interest in the development of NLRP3-targeted small molecule inhibitors as a promising therapeutic approach for gout. To assess the advancements in NLRP3 inflammasome inhibitors for gout treatment, this review offers a comprehensive analysis and evaluation of current clinical candidates and other inhibitors targeting NLRP3 inflammasome from a chemical structure standpoint, with the goal of identifying more efficacious options for clinical management of gout.