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The aim of this work is to provide a critical review of plant furanocoumarins from different points of view, including their chemistry and biosynthetic pathways to their extraction, analysis, and synthesis, to the main biological activities found for these active compounds, in order to highlight their potential within pharmaceutical science. The limits and the possible improvements needed for research involving these molecules are also highlighted and discussed.

Cancer is one of the most extreme medical conditions in both developing and developed countries around the world, causing millions of deaths each year. Chemotherapy and/or radiotherapy are key for treatment approaches, but both have numerous adverse health effects. Furthermore, the resistance of cancerous cells to anticancer medication leads to treatment failure. The rising burden of cancer overall requires novel efficacious treatment modalities. Natural medications offer feasible alternative options against malignancy in contrast to western medication. Furanocoumarins’ defensive and restorative impacts have been observed in leukemia, glioma, breast, lung, renal, liver, colon, cervical, ovarian, and prostate malignancies. Experimental findings have shown that furanocoumarins activate multiple signaling pathways, leading to apoptosis, autophagy, antioxidant, antimetastatic, and cell cycle arrest in malignant cells. Additionally, furanocoumarins have been shown to have chemo preventive and chemotherapeutic synergistic potential when used in combination with other anticancer drugs. Here, we address different pathways which are activated by furanocoumarins and their therapeutic efficacy in various tumors. Ideally, this review will trigger interest in furanocoumarins and their potential efficacy and safety as a cancer lessening agents.

Breast cancer is one of the biggest global dilemmas and its current therapy is to target the hormone receptors by the use of partial agonists/antagonists. Potent drugs for breast cancer treatment are Tamoxifen, Trastuzumab, Paclitaxel, etc. which show adverse effects and resistance in patients. The aim of the study has been on certain phytochemicals which has potent actions on ERα, PR, EGFR and mTOR inhibition. The current study is performed by the use of molecular docking as protein-ligand interactions play a vital role in drug design. The 3D structures of ERα, PR, EGFR and mTOR were obtained from the protein data bank and docked with 23 3D PubChem structures of furanocoumarin compounds using FlexX. Drug-likeness property was checked by applying the Lipinski’s rule of five on the furanocoumarins to evaluate anti-breast cancer activity. Antagonist and inhibition assay of ERα, EGFR and mTOR respectively has been performed using appropriate in-vitro techniques. The results confirm that Xanthotoxol has the best docking score for breast cancer followed by Bergapten, Angelicin, Psoralen and Isoimperatorin. Further, the in-vitro results also validate the molecular docking analysis. This study suggests that the selected furanocoumarins can be further investigated and evaluated for breast cancer treatment and management strategies.

Ruta chalepensis L. (Rutaceae), a perennial herb with wild and cultivated habitats, is well known for its traditional uses as an anti-inflammatory, analgesic, antipyretic agent, and in the treatment of rheumatism, nerve diseases, neuralgia, dropsy, convulsions and mental disorders. The antimicrobial activities of the crude extracts from the fruits, leaves, stem and roots of R. chalepensis were initially evaluated against two Gram-positive and two Gram-negative bacterial strains and a strain of the fungus Candida albicans. Phytochemical investigation afforded 19 compounds, including alkaloids, coumarins, flavonoid glycosides, a cinnamic acid derivative and a long-chain alkane. These compounds were tested against a panel of methicillin-resistant Staphylococcus aureus (MRSA) strains, i.e., ATCC 25923, SA-1199B, XU212, MRSA-274819 and EMRSA-15. The MIC values of the active compounds, chalepin (9), chalepensin (10), rutamarin (11), rutin 3′-methyl ether (14), rutin 7,4′-dimethyl ether (15), 6-hydroxy-rutin 3′,7-dimethyl ether (16) and arborinine (18) were in the range of 32–128 µg/mL against the tested MRSA strains. Compounds 10 and 16 were the most active compounds from R. chalepensis, and were active against four out of six tested MRSA strains, and in silico studies were performed on these compounds. The anti-MRSA activity of compound 16 was comparable to that of the positive control norfloxacin (MICs 32 vs 16 μg/mL, respectively) against the MRSA strain XU212, which is a Kuwaiti hospital isolate that possesses the TetK tetracycline efflux pump. This is the first report on the anti-MRSA property of compounds isolated from R. chalepensis and relevant in silico studies on the most active compounds.

The purpose of this study was to establish an in vitro incubation system and an in vivo model to investigate the potential kinetic interactions of macitentan with imperatorin and curcumin, and to validate the potential inhibitory mechanisms using molecular docking. In vitro, the enzyme kinetic profile of macitentan was explored in rat liver microsomes (RLM) and human liver microsomes (HLM). Furthermore, molecular docking technique was used to study the sites of action of macitentan, imperatorin, and curcumin with CYP 3A4. In vivo, the pharmacokinetic parameters of macitentan were investigated in Sprague-Dawley (SD) rats administered the drug orally, both as a single agent and in combination with imperatorin and curcumin. In vitro, the results indicated that imperatorin and curcumin could inhibit the metabolism of macitentan, with IC values of 6.58 μM and 10.86 μM in RLM and 6.97 μM and 5.71 μM in HLM, respectively. And in the study of inhibition type, in RLM, the inhibition types of imperatorin and curcumin on macitentan were mixed and non-competitive, respectively; in HLM, the inhibition types of imperatorin and curcumin on macitentan were both mixed. Furthermore, additional molecular docking studies demonstrated that both imperatorin and curcumin occupied the CYP3A4 site. In vivo, the result showed significant increases in AUC , AUC , T , t , and C for macitentan while a decrease in CL when combined with imperatorin. The metabolite ACT-132577 exhibited substantial increases in t , T , and C . Combined with curcumin, the AUC and T of macitentan were significantly increased, while CL was significantly decreased. Conversely, the metabolite ACT-132577 exhibited a substantial decrease in CL , accompanied by notable increases in AUC and T . In vitro and in vivo studies revealed that imperatorin and curcumin exhibited inhibitory effects on the metabolism of macitentan. Furthermore, molecular docking revealed that the metabolic inhibition of macitentan by imperatorin and curcumin occurred through binding to the site on CYP3A4. However, further investigation is necessary to ascertain whether this phenomenon will occur in humans.

Melanoma is a malignant skin cancer associated with high mortality rates and drug resistance, posing a significant threat to human health. The combination of chemotherapy and photodynamic therapy (PDT) represents a promising strategy to enhance antitumor efficacy through synergistic anti-cancer effects. Topical delivery of chemotherapeutic drugs and photosensitizers (PS) offers a non-invasive and safe way to treat melanoma. However, the effectiveness of these treatments is often hindered by challenges such as limited skin permeability and instability of the PS. In this study, transfersomes (TFS) were designed to facilitate transdermal delivery of the chemotherapeutic drug 5-Fluorouracil (5-FU) and the PS Imperatorin (IMP) for combined chemo-photodynamic therapy for melanoma. The cytotoxic and phototoxic effects of TFS-mediated PDT (TFS-UVA) were investigated in A375 cells and nude mice. The study also demonstrated that TFS-UVA generated intracellular ROS, induced G2/ M phase cell cycle arrest, and promoted cell apoptosis. In conclusion, this study indicated that 5-FU/ IMP-TFS serves as an effective transdermal therapeutic strategy for chemo-PDT in treating melanoma.

Furanocoumarins, known for their diverse bioactivity, were chemically modified to develop new derivatives with potential anticancer properties. This study reports the synthesis and comprehensive biological evaluation of seven aminoalkyl furanocoumarin derivatives. In vitro cytotoxicity was assessed against four human cancer cell lines (HTB-140, A549, HeLa, SW620) and a normal keratinocyte line (HaCaT) using MTT and LDH assays. Compounds 4 and 6 demonstrated the strongest antiproliferative effects, particularly against SW620 and HTB-140 cells, with IC₅₀ values around 11–18 µM, indicating potent anticancer activity. Flow cytometry revealed that these effects were largely mediated through apoptosis, not nonspecific toxicity. Molecular docking studies identified interactions with EGFR and Bcl-2 family proteins, suggesting a pro-apoptotic mechanism, though additional pathways may contribute to their selectivity. Importantly, antimicrobial screening showed negligible activity against representative Gram-positive and Gram-negative strains, indicating a low risk of microbiota disruption - an important feature for cancer therapy. These findings position furanocoumarin derivatives, particularly compounds 4 and 6 , as promising lead structures for the development of selective, microbiota-sparing anticancer agents.

The scope of this review encompasses the importance of furocoumarins and the most important developments in this field that have been made in recent years, with particular emphasis placed on the aspects related to medicinal chemistry. A concise and exhaustive overview is given regarding the methods used for the synthesis of these compounds, new furocoumarins isolated from natural sources, and the most significant biological properties associated with these molecules. The section describing the synthetic methods is organized on the basis of the key step used for the formation of the two different oxygenated rings. In this respect there are three possibilities: (i) formation of the furan ring onto the coumarin, (ii) formation of the pyrone ring onto the benzofuran and (iii) the simultaneous formation of both oxygenated rings onto a benzene unit. The most recent preparative approaches are discussed along with modifications or improvements to methods that, though not particularly new, are still commonly used. The recently discovered natural furocoumarins are focused and presented in tables that provide information about its structure and source. The discussion of the biological importance of furocoumarins mainly focuses on their more relevant applications in photochemotherapy, but also provides examples of their versatility in a range of applications in the fields of biology and pharmacology.

Background/Objectives: Furocoumarins, chemical compounds found in many plant species, have a photosensitizing effect on the skin when applied topically and, by interacting with ultraviolet radiation (UVR), stimulate melanoma cells to proliferate. Whether dietary intake of furocoumarins acts as a melanoma risk factor has been investigated in several epidemiological studies, which are synthesized in our systematic review. Methods: The study protocol was registered with PROSPERO (registration number: CRD42023428596). We conducted an in-depth literature search in three databases coupled with forward and backward citation tracking and expert consultations to identify all epidemiological studies, irrespective of their design, addressing the association between a furocoumarin-containing diet and melanoma risk. We extracted information on the study details and results in a standardized manner and evaluated the risk of bias of the results using the Joanna Briggs Institute’s critical appraisal tools. Results: We identified 20 publications based on 19 different studies providing information on the association between dietary furocoumarin intake and melanoma risk. We refrained from a meta-analytical synthesis of the results because of the large heterogeneity in exposure assessment, operationalization of furocoumarin intake in the analyses, and analytical methods of the studies. In a qualitative synthesis, we found moderate evidence supporting the notion that dietary furocoumarin intake at higher levels acts as a risk factor for cutaneous melanoma. Conclusions: Our systematic review provides an overview of the current epidemiological evidence, but it could not clearly answer whether and to what extent dietary furocoumarin intake increases melanoma risk. Future epidemiological analyses focusing on this topic require more comprehensive dietary and UVR exposure data to better characterize the individual total furocoumarin intake and its interplay with UVR exposure patterns.

Rationale Imperatorin, a naturally occurring furanocoumarin, inactivates gamma-aminobutyric acid transaminase and inhibits acetylcholinesterase activity. Objectives The purpose of our experiment was to examine the influence of imperatorin on cognitive impairment and oxidative stress in the brain induced by scopolamine in male Swiss mice. Methods In the present studies, we used scopolamine-invoke memory deficit measured in passive avoidance (PA) paradigm as an animal model of Alzheimer disease (AD). Results Our finding revealed that imperatorin administered acutely at the doses of 5 and 10 mg/kg prior to the injection of scopolamine (1 mg/kg) improved memory acquisition and consolidation impaired by scopolamine. Furthermore, repeatable (7 days, twice daily) administration of the highest dose of imperatorin (10 mg/kg) significantly attenuated the effects of scopolamine on memory acquisition, whereas the doses of 5 and 10 mg/kg of this furanocoumarin were effective when memory consolidation was measured. Imperatorin, administered with scopolamine, increased antioxidant enzymes activity and decreased concentration of malondiamide, an indicator of lipid peroxidation level. Conclusions These results demonstrate that imperatorin may offer protection against scopolamine-induced memory impairments and possesses antioxidant properties, thus after further preclinical and clinical studies this compound may provide an interesting approach in pharmacotherapy, as well as prophylactics of AD.