Flavonoids, a series of compounds with a C6-C3-C6 structure, mostly originate from plant metabolism. Flavonoids have shown beneficial effects on many aspects of human physiology and health. Recently, many flavonoids with various activities have been discovered, which has led to more and more studies focusing on their physiological and pharmacodynamic activities. The anticancer and anti-viral activities especially have gained the attention of many researchers. Therefore, the discovery and development of flavonoids as anti-disease drugs has great potential and may make a significant contribution to fighting diseases. This review focus on the discovery and development of flavonoids in medicinal chemistry in recent years.

Comment in Curr Top Med Chem. 2022 Mar 4;22(4):268.

Pyrimidine-fused derivatives that are the inextricable part of DNA and RNA play a key role in the normal life cycle of cells. Pyrimidine-fused dinitrogenous penta-heterocycles, including pyrazolopyrimidines and imidazopyrimidines are a special class of pyrimidine-fused compounds contributing to an important portion in anti-cancer drug discovery, which has been discovered as the core structure for promising anti-cancer agents used in the clinic or clinical evaluations. Pyrimidinefused dinitrogenous penta-heterocycles have become one privileged scaffold for anti-cancer drug discovery. This review consists of the recent progress of pyrimidine-fused dinitrogenous pentaheterocycles as anti-cancer agents and their synthetic strategies. In addition, this review also summarizes some key structure-activity relationships (SARs) of pyrimidine-fused dinitrogenous pentaheterocycle derivatives as anti-cancer agents.

Comment in Curr Top Med Chem. 2022 Mar 4;22(5):331-332.

Comment in Curr Top Med Chem. 2022 Mar 4;22(5):331-332.

Comment in Curr Top Med Chem. 2022 Mar 4;22(5):331-332.

Comment in Curr Top Med Chem. 2022 Mar 4;22(5):331-332.

Comment in Curr Top Med Chem. 2022 Mar 4;22(5):331-332.

BACKGROUND: In a study recently published by our research group, the isoxazoline-acylhydrazone derivatives R-99 and R-123 presented promising antinociceptive activity. However, the mechanism of action of this compound is still unknown. OBJECTIVE: This study aimed to assess the mechanisms involved in the antinociceptive activity of these compounds in chemical models of pain. METHODS: Animals were orally pretreated and evaluated in the acetic acid-, formalin-, capsaicin-, carrageenan- and Complete Freund's Adjuvant (CFA)-induced pain models in mice. The effects of the compounds after pretreatment with naloxone, prazosin, yohimbine, atropine, L-arginine, or glibenclamide were studied, using the acetic acid-induced writhing test to verify the possible involvement of opioid, α1-adrenergic, α2-adrenergic or cholinergic receptors, and nitric oxide or potassium channels pathways, respectively. RESULTS: R-99 and R-123 compounds showed significant antinociceptive activity on pain models induced by acetic acid, formalin, and capsaicin. Both compounds decreased the mechanical hyperalgesia induced by carrageenan or CFA in mice. The antinociceptive effects of R-99 and R-123 on the acetic acid-induced writhing test were significantly attenuated by pretreatment with naloxone, yohimbine or atropine. R-99 also showed an attenuated response after pretreatment with atropine and glibenclamide. However, on the pretreatment with prazosin, there was no change in the animals' response to both compounds. CONCLUSION: R-99 and R-123 showed antinociceptive effects related to mechanisms that involve, at least in part, interaction with the opioid and adrenergic systems and TRPV1 pathways. The compound R-99 also interacts with the cholinergic pathways and potassium channels.

INTRODUCTION: Curcuma longa L. has been associated with different antioxidant, antiinflammatory, bactericidal and anticancer effects, but the mechanisms of the effects are not yet clearly understood. This study aimed to investigate the key targets and the effect of potential molecular mechanisms of Curcuma longa L. extracts on glioma using different network pharmacology analysis approaches. METHODS: The components of Curcuma longa were extracted by gas chromatography-mass spectrometry (GC-MS), and the active components related to the occurrence and development of glioma were determined by traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) database, and the same targets of the active components and glioma were screened by network pharmacology approach. Then, the protein's function and regulatory pathway of the common targets were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The protein's action and regulatory pathway of the common targets were analyzed with the Cytoscape package using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database to construct the target interaction network through which the key targets were identified. RESULTS: GC-MS combined with TCMSP database was used to identify the active components related to the occurrence and development of glioma in Curcuma longa. Finally, we identified the active components 1-(1,5-Dimethyl-4-hexenyl)-4-methyl benzene and Zingiberene. At the same time, 190 target genes of Curcuma longa extracts on glioma were obtained using the Venn diagram. The results of GO analysis showed that the biological processes involved included a response to stimulation, metabolic process, inflammatory process, cell differentiation, and regulation of biological processes. KEGG analysis showed that the PI3K-Akt signaling pathway, MAPK signaling pathway, Th17 cell differentiation, and proteoglycan pathway might be involved in cancer. Further analyses showed that the IL-17 signaling pathway and Interleukin-4 and interleukin-13 signaling were involved in the inflammatory pathway. The analysis of key nodes showed that GSK3B, MAPK14, HSP90AA1, MAPK3 and MAPK8 were IL-17 signaling pathways, while HIF1A and JAK3 were Interleukin-4 and interleukin-13 signaling pathways. CONCLUSION: Curcuma longa extracts can regulate the occurrence and development of glioma by regulating the immune-inflammatory responses.

AIMS: Herein, molecular docking approaches and DFT ab initio simulations were combined for the first time, to study the key interactions of cyclodextrins (CDs: α-CD, β-CD, and γ-CD) family with potential pharmacological relevance and the multidrug resistance P-gp protein toward efficient drug-delivery applications. BACKGROUND: The treatment of neurological disorders and cancer therapy where the multiple drug-resistance phenomenon-mediated by the P-gp protein constitutes the fundamental cause of unsuccessful therapies. OBJECTIVE: Undercover the docking mechanism of the CDs and the P-gp-. METHODS: Use of the computational docking methodology to reach the main aim. RESULT: The observed docking-mechanism of the CDs on the P-gp were fundamentally based on hybrid backbone/side-chain hydrophobic interactions, and also hybrid electrostatic/side-chain interactions of the OH-motifs of the CD-ligands with acceptor and donor properties which theoretically could induce local perturbations in the TMD/P-gp inter-residues network modulating to the ligand extrusion from the blood-brain-barrier. CONCLUSION: These theoretical results open new horizons for the evaluation of new nanotherapeutic drugs with potential pharmacological relevance for efficient drug-delivery for nanomedicine applications. P-gp residues were conformationally favored. Despite the structural differences, all the cyclodextrins exhibit very close Gibbs free binding energy values (or affinity) by the P-gp binding site (transmembrane domains - TMDs). The obtained theoretical docking-mechanism of the CDs on the P-gp were fundamentally based on hybrid backbone/side-chain hydrophobic interactions, and also hybrid electrostatic/side-chain interactions of the OH-motifs of the CD-ligands with acceptor and donor properties which theoretically could induce allosteric local-perturbations in the TMDs-inter-residues network of P-gp modulating to the CD-ligand extrusion from the blood-brain-barrier (or cancer cells). Finally, these theoretical results open new horizons for the evaluation of new nanotherapeutic drugs with potential pharmacological relevance for efficient drug-delivery applications and precision nanomedicine.