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Crocetin and related oxygen diffusion-enhancing compounds: Review of chemical synthesis, pharmacology, clinical development, and novel therapeutic applications.

ABSTRACT: The current pandemic forced us to introspect and revisit our armamentarium of medicinal agents which could be life-saving in emergency situations. Oxygen diffusion-enhancing compounds represent one such class of potential therapeutic agents, particularly in ischemic conditions. As rewarding as the name suggests, these agents, represented by the most advanced and first-in-class molecule, trans-sodium crocetinate (TSC), are the subject of intense clinical investigation, including Phase 1b/2b clinical trials for COVID-19. Being a successor of a natural product, crocetin, TSC is being investigated for various cancers as a radiosensitizer owing to its oxygen diffusion enhancement capability. The unique properties of TSC make it a promising therapeutic agent for various ailments such as hemorrhagic shock, stroke, heart attack, among others. The present review outlines various (bio)synthetic strategies, pharmacological aspects, clinical overview and potential therapeutic benefits of crocetin and related compounds including TSC. The recent literature focusing on the delivery aspects of these compounds is covered as well to paint the complete picture to the curious reader. Given the potential TSC holds as a first-in-class agent, small- and/or macromolecular therapeutics based on the core concept of improved oxygen diffusion from blood to the surrounding tissues where it is needed the most, will be developed in future and satisfy the unmet medical need for many diseases and disorders.

SUBMITTER: Shah HM

PROVIDER: S-EPMC8273373 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hibiscus cannabinus L. leaves (HCLLs) are considered a favorable source of natural antiobesity substances. However, actual bioactive compound(s) in it and their mechanism(s) against obesity have not been confirmed. Hence, network pharmacology was conducted to identify its key compounds and mechanism(s) against obesity. Compounds in HCLLs were identified through GC-MS analysis and screened by Lipinski's rule. Genes related to the selected compounds and obesity were obtained from public databases, and overlapping genes between HCLL compound-related genes and obesity target genes were selected using a Venn diagram. The networking between selected compounds and overlapping genes was then constructed, visualized, and analyzed by RStudio. Finally, the binding affinity between compounds and genes was evaluated via molecular docking (MD). A total of 30 compounds in HCLLs were detected via GC-MS, and Lipinski's rule accepted all compounds. The compound-related genes (570 genes) and obesity targeted genes (3028 genes) were identified, and between them, 64 overlapping genes were selected. Gene Set Enrichment Analysis (GSEA) displayed that the mechanisms of HCLLs against obesity were associated with 13 signaling pathways on 22 compounds in HCLLs. Superficially, AKT1, vitamin E, and RAS signaling pathways were noted as a hub gene, an uppermost bioactive compound, and a hub signaling pathway, respectively. However, the binding affinity of ligands and proteins on the RAS signaling pathway was very low; instead, the PPAR signalling pathway was evaluated with potent efficacy against obesity through MD. On the PPAR signaling pathway, α-amyrin was found as the most significant compound for the amelioration of obesity. α-Amyrin manifested the strongest binding affinity on six target proteins associated with the PPAR signaling pathway. Our study suggests that an auxiliary (PPAR) signaling pathway of HCLLs might intervene efficiently against obesity over the hub (RAS) signaling pathway.

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Crocetin and related oxygen diffusion-enhancing compounds: Review of chemical synthesis, pharmacology, clinical development, and novel therapeutic applications.

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