Vitamin K epoxide reductase complex (VKORC1)
Among the various pharmacological effects of Coumarins in Plants and their derivatives, the research on anticoagulant effect is the most mature. As early as the 1970s, Bell et al. proposed that anticoagulant drugs such as coumarin play an anticoagulant effect by inhibiting the reduction of vitamin K 2,3-epoxide (KO) to vitamin K hydrogen type reaction of. Later, it was discovered that warfarin and other coumarin drugs inhibited the activity of the key enzyme for KO reduction, which is vitamin K epoxide reductase (VKOR).
There are currently 3 anticoagulant drugs of the Coumarins in Plants category on the market, namely warfarin potassium, warfarin sodium and Phenprocoumon, all of which were launched earlier. Among them, the clinical trials of warfarin sodium are more detailed. The results of 6 clinical studies showed that warfarin sodium was significantly (p<0.05) superior to placebo, dipyridamole/aspirin and pentoxifylline/aspirin in resisting systemic thrombosis.
DNA gyrase B subunit (gyrB)
In the process of DNA replication, the negative supercoil created by DNA helicase (gyrase) can stabilize the separation of DNA, prevent excessive and non-template double-stranded coiling, and ensure the smooth progress of DNA replication. As a result, people have developed antibacterial drugs targeting gyrase: quinolones and coumarins. Quinolones act on the A subunit of gyrase, while coumarins act on the B subunit of gyrase.
The only currently marketed gyrB inhibitor is the coumarin drug novobiocin sodium. The drug is active against gram-positive bacteria such as Staphylococcus aureus (including methicillin-resistant strains) and other staphylococci; it is often resistant to Enterococcus faecalis and may be susceptible to Enterococcus faecium. Susceptible to Gram-negative bacteria including Haemophilus influenzae, Neisseria, and some Proteus species, but most Enterobacteriaceae are resistant to it. Novobiocin is mainly a bacteriostatic agent, but it also has a bactericidal effect on sensitive bacteria at high concentrations. Novobiocin has the effect of inhibiting DNA helicase and can also remove plasmids, but it is prone to drug resistance in vitro or during treatment. Although novobiocin can be used alone or in combination with other drugs such as rifampicin and sodium fusidate to treat infections caused by staphylococcus and other sensitive bacteria, but now due to the problems of drug resistance and toxicity, novobiocin has been basically replaced by other drugs. Novobiocin is a highly effective sensitizer, and related hypersensitivity reactions include rash, fever, and itching, and Stevens-Johnson syndrome and pneumonia can occur in more severe cases. Jaundice and liver damage can also occur, but jaundice is mainly caused by the yellow metabolite of the drug and partly by hyperbilirubinemia. Other adverse reactions included eosinophilia, leukopenia, thrombocytopenia, agranulocytosis, and hemolytic anemia; gastrointestinal reactions were common.
Another major use of Coumarins in Plants listed drugs is as a drug for the treatment of psoriasis and vitiligo. Methoxsalen and trimethalin, which were approved by the US Food and Drug Administration (FDA) in 1954, were developed by Valeant as psoralens, which can be used as photosensitizers in photochemotherapy or PUVA therapy. In addition, methoxsalen can also be selectively used for atopic dermatitis, multimorphic light eruption, T-cell lymphoma (such as mycosis fungoides), etc. In a study of PUVA therapy in 41 patients with psoriasis, administering methoxsalen 25 mg/m2 to the patients according to the body surface can make their blood drug concentrations more consistent, and relatively reduce the risk of obesity caused by the patients. Potential for overdose or underdose due to discrepancies.
Transforming growth factor beta 1 (TGF-beta1)
Transforming growth factor-beta (TGF-beta) was identified by DeLarco and Todaro in 1978 from the culture medium of mouse sarcoma virus cell strains, and was named transforming growth factor because of its characteristic of cell transformation. TGF-β is an important cytokine in organisms, which has a variety of biological effects, including embryonic development, wound healing, chemotaxis and cell cycle regulation. Studies have found that TGF-β can stimulate tissue fibrosis and extracellular matrix deposition, disrupt immune function, stimulate angiogenesis and promote epithelial-mesenchymal transition.
Coumarins in Plants amide derivative nicousamide (nicousamide) is a clinical phase II drug intended for renal dysfunction, including the treatment of diabetic nephropathy and hypertensive nephropathy. Studies have shown that nicousamide inhibits or slows down the process of renal fibrosis by inhibiting the phosphorylation of TGF-β receptor and its downstream proteins.