Chemical Biology & Drug Design最新文献

The biphenyl scaffold represents a prominent privileged structure within the realms of organic chemistry and drug development. Biphenyl derivatives have demonstrated notable biological activities, including antimicrobial, anti-inflammatory, anti-HIV, and the treatment of neuropathic pain. Importantly, their anticancer abilities should not be underestimated. In this context, the present study involves the design and synthesis of a series of biphenyl derivatives featuring an additional privileged structure, namely the quinoline core. We have also diversified the substituents attached to the benzyloxy group at either the meta or para position of the biphenyl ring categorized into two distinct groups: [4,3′]biphenylaminoquinoline-substituted and [3,3′]biphenylaminoquinoline-substituted compounds. We embarked on an assessment of the cytotoxic activities of these derivatives in colorectal cancer cell line SW480 and prostate cancer cell line DU145 for exploring the structure–activity relationship. Furthermore, we determined the IC₅₀ values of selected compounds that exhibited superior inhibitory effects on cell viability against SW480, DU145 cells, as well as MDA-MB-231 and MiaPaCa-2 cells. Notably, [3,3′]biphenylaminoquinoline derivative 7j displayed the most potent cytotoxicity against these four cancer cell lines, SW480, DU145, MDA-MB-231, and MiaPaCa-2, with IC₅₀ values of 1.05 μM, 0.98 μM, 0.38 μM, and 0.17 μM, respectively. This highly promising outcome underscores the potential of [3,3′]biphenylaminoquinoline 7j for further investigation as a prospective anticancer agent in future research endeavors.

This study investigates the molecular mechanism of Ma Huang-Ku Xing Ren, a traditional Chinese medicine formula, in treating pediatric pneumonia. The focus is on the regulation of caspase-3 activation and reduction of alveolar macrophage necrosis through network pharmacology and bioinformatics analyses of Ephedra and bitter almond components. Active compounds and targets from ephedrine and bitter almond were obtained using TCMSP, TCMID, and GeneCards databases, identifying pediatric pneumonia-related genes. A protein–protein interaction (PPI) network was constructed, and core targets were screened. GO and KEGG pathway enrichment analyses identified relevant genes and pathways. An acute pneumonia mouse model was created using the lipopolysaccharide (LPS) inhalation method, with caspase-3 overexpression induced by a lentivirus. The mice were treated with Ephedra and bitter almond through gastric lavage. Lung tissue damage, inflammatory markers (IL-18 and IL-1β), and cell death-related gene activation were assessed through H&E staining, ELISA, western blot, flow cytometry, and immunofluorescence. The study identified 128 active compounds and 121 gene targets from Ephedra and bitter almond. The PPI network revealed 13 core proteins, and pathway analysis indicated involvement in inflammation, apoptosis, and cell necrosis, particularly the caspase-3 pathway. In vivo results showed that Ephedra and bitter almond treatment significantly mitigated LPS-induced lung injury in mice, reducing lung injury scores and inflammatory marker levels. It also decreased caspase-3 activity and cell death in alveolar macrophages. In conclusion, the active ingredients of Ma Huang-Ku Xing Ren, particularly targeting caspase-3, may effectively treat pediatric pneumonia by reducing apoptosis in alveolar macrophages, as demonstrated by both network pharmacology, bioinformatics analyses, and experimental data.

With the increasing aging population, rational design of drugs for Alzheimer's disease (AD) treatment has become an important research area. Based on the multifunctional design strategy, four diosmetin derivatives (1–4) were designed, synthesized, and characterized by ¹H NMR, ¹³C NMR, and MS. Docking study was firstly applied to substantiate the design strategies and then the biological activities including cholinesterase inhibition, metal chelation, antioxidation and β-amyloid (Aβ) aggregation inhibition in vitro were evaluated. The results showed that 1–4 had good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, metal chelation (selective chelation of Cu²⁺ ions), antioxidation, self-induced, Cu²⁺-induced, and AChE-induced Aβ aggregation inhibition activities, and suitable blood–brain barrier (BBB) permeability. Especially, compound 3 had the strongest inhibitory effect on AChE (10⁻⁸ M magnitude) and BuChE (10⁻⁷ M magnitude) and showed the best inhibition on AChE-induced Aβ aggregation with 66.14% inhibition ratio. Furthermore, compound 3 could also reduce intracellular reactive oxygen species (ROS) levels in Caenorhabditis elegans and had lower cytotoxicity. In summary, 3 might be considered as a potential multifunctional anti-AD ligand.

β-Carboline nucleus is therapeutically valuable in medicinal chemistry for the treatment of varied number of diseases, most importantly cancer. The potent and wide-ranging activity of β-carboline has established them as imperative pharmacological scaffolds especially in the cancer treatment. Numerous derivatives such as Tetrahydro β-carbolines, metal complexed β-carbolines, mono, di and tri substituted β-carbolines have been reported to possess dynamic anticancer activity. These different substituted β-carboline derivatives had shown different mechanism of action and plays important role in anticancer drug discovery and development. The review is an update of the chemistry of β-carbolines, both synthetic and natural origin acting through various targets against cancerous cells. In addition to this, studies of multitarget molecules designed by coupling β-carbolines along with other mechanisms for treatment of neoplasm are also summarized.

Aktepe, N., Baran, A., Atalar, M. N., Baran, F., Keskin, C., Taşkin, A., Yavuz, Ö., Demirtaş, İ., Oğuz, E., & Jahan, I. (2023). Analysis of bioactive compounds using LC–ESI–MS/MS, cytotoxic, antimicrobial effects, and enzyme activities from Cyclotrichium origanifolium. Chemical Biology & Drug Design, 101, 740–748. https://doi.org/10.1111/cbdd.14177

The affiliation information for Israt Jahan, “Department of Molecular Biology and Genetics, Faculty of Science, Dicle University, Diyarbakir, Turkey” was incorrect.

The correct affiliation should be “Department of Health Care Services, Vocational School of Health Services, Mardin Artuklu University, 47200 Mardin, Turkiye”

We apologize for this error.

In the above article, the title “Brucine D restrains colorectal cancer tumorigenesis and autophagy by downregulating circ_0068464” was incorrect. This should have read “Bruceine D restrains colorectal cancer tumorigenesis and autophagy by downregulating circ_0068464.”

The online version of this article has been corrected accordingly.

We apologize for this error.

An early exploration of the benzothiazole class against two kinetoplastid parasites, Leishmania infantum and Trypanosoma cruzi, has been performed after the identification of a benzothiazole derivative as a suitable antileishmanial initial hit. The first series of derivatives focused on the acyl fragment of its class, evaluating diverse linear and cyclic, alkyl and aromatic substituents, and identified two other potent compounds, the phenyl and cyclohexyl derivatives. Subsequently, new compounds were designed to assess the impact of the presence of diverse substituents on the benzothiazole ring or the replacement of the endocyclic sulfur by other heteroatoms. All compounds showed relatively low cytotoxicity, resulting in decent selectivity indexes for the most active compounds. Ultimately, the in vitro ADME properties of these compounds were assessed, revealing a satisfying water solubility, gastrointestinal permeability, despite their low metabolic stability and high lipophilicity. Consequently, compounds 5 and 6 were identified as promising hits for further hit-to-lead exploration within this benzothiazole class against L. infantum, thus providing promising starting points for the development of antileishmanial candidates.

Ovarian cancer is the most deadly female gynaecological malignancy in developed countries and new treatments are urgently needed. The luteinising hormone releasing hormone (LHRH) peptide drug conjugate Zoptarelin doxorubicin is one such potential new drug modality that entered clinical trials for treating LHRH receptor-positive gynaecological cancers. However, development stopped after disappointing Phase 3 results in 2017. We believe the lack of efficacy was due to linker instability and payload potency. In this work, we replaced its linker-toxin with vedotin (MC-VC-PABC-MMAE), yielding the novel peptide drug conjugate D-Cys6-LHRH vedotin. A GI₅₀ and cell specificity comparison against cancerous and non-cancerous ovarian cell lines showed significantly superior bioactivity and selectivity over Zoptarelin doxorubicin (GI₅₀ 4 vs. 453 nM) and other chemotherapeutic drugs used for treating ovarian cancers. Our results suggest D-Cys6-LHRH vedotin can potentially be used as a treatment for ovarian cancer.

Corrigendum to ‘Sinigrin improves cerebral ischaemia-reperfusion injury by inhibiting the TLR4 pathway-mediated oxidative stress.’ Chem Biol Drug Des. 2024 Feb;103(2):e14480. doi: 10.1111/cbdd.14480

Shenglong Guo¹, Qi Lei¹, Qian Yang¹, Ruili Chen¹

¹Department II of Neurology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P.R. China

The above article was published with several errors in the author information.

Qi Lei is not co-first author as listed.

Qian Yang is not a co-correspondence author.

The correct correspondence details are

Correspondence

Ruili Chen, Department II of Neurology, Shaanxi Provincial People's Hospital, No. 256, Youyi West Road, Xi'an, 710068, Shaanxi, P.R. China.

Email: [email protected]

The authors would like to apologize for any inconvenience caused.

The epidermal growth factor receptor (EGFR) has been well validated as a therapeutic target for anticancer drug discovery. Osimertinib has become the first globally accessible third-generation EGFR inhibitor, representing one of the most advanced developments in non-small-cell lung cancer (NSCLC) therapy. However, a tertiary Cys797 to Ser797 (C797S) point mutation has hampered osimertinib treatment in patients with advanced EGFR-mutated NSCLC. Several classes of fourth-generation EGFR inhibitors were consequently discovered with the aim of overcoming the EGFR^C797S mutation-mediated resistance. However, no clinical efficacy data of the fourth-generation EGFR inhibitors were reported to date, and EGFR^C797S mutation-mediated resistance remains an “unmet clinical need.” Proteolysis-targeting chimeric molecules (PROTACs) obtained from EGFR-TKIs have been developed to target drug resistance EGFR in NSCLC. Some PROTACs are from nature products. These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition, and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the resistance, and mutations of EGFR, and then mainly focus on the recent advances of EGFR-targeting degraders along with its advantages and outstanding challenges.