Revitalizing antimicrobial strategies: paromomycin and dicoumarol repurposed as potent inhibitors of M.tb's replication machinery via targeting the vital protein DnaN

Article

Author: Khan, Areeba ; Sharma, Rahul ; Grover, Sonam ; Agarwal, Meetu ; Jamal, Salma ; Ali, Waseem ; Dwivedi, Ved Prakash ; Gangwar, Rishabh ; Grover, Abhinav ; Ahmad, Zahoor ; Wani, Zubair Ahmad ; Mubarak, Mohamad Mosa ; Bhaskar, Ashima ; Sheikh, Javaid Ahmad

01 Sep 2024·Redox Biology

DPP9 regulates NQO1 and ROS to promote resistance to chemotherapy in liver cancer cells

Article

Author: Zhou, Yunjiang ; Hu, Rong ; Chen, Yaxin ; Tan, Yingying ; Li, Xingyan ; Chen, Chi ; Huang, Xing ; Cao, Mengran ; Yang, Mengdi ; Xuan, Chenyuan

Chemotherapy has been the standard treatment for liver cancer. However, intrinsic or acquired drug resistance remains a major barrier to successful treatment. At present, the underlying molecular mechanisms of chemoresistance in liver cancer have not been elucidated. Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family that has been found to be highly expressed in a variety of tumors, including liver cancer. It is unclear whether DPP9 affects chemoresistance in liver cancer. In this study, we find that DPP9 weakens the responses of liver cancer cells to chemotherapy drugs by up-regulating NQO1 and inhibiting intracellular ROS levels. In terms of mechanism, DPP9 inhibits ubiquitin-mediated degradation of NRF2 protein by binding to KEAP1, up-regulates NRF2 protein levels, promotes mRNA transcription of NQO1, and inhibits intracellular ROS levels. In addition, the NQO1 inhibitor dicoumarol can enhance the efficacy of chemotherapy drugs in liver cancer cells. Collectively, our findings suggest that inhibiting DPP9/NQO1 signaling can serve as a potential therapeutic strategy for liver cancer.

01 Sep 2024·Bioorganic & Medicinal Chemistry Letters

Synthesis and evaluation of 3-hydroxyquinolin-2(1H)-one derivatives as inhibitors of tyrosinase

Article

Author: Cloete, Stephanus J ; Jacobs, Maria E ; Petzer, Anél ; Petzer, Jacobus P ; Pretorius, Judey ; Crous, Chantalle

The tyrosinase (TYR) enzyme catalyses sequential reactions in the melanogenesis pathway: l-tyrosine is oxidised to yield L-3,4-dihydroxyphenylalanine (l-dopa), which in turn is converted to dopaquinone. These two reactions are the first two steps of melanin biosynthesis and are rate limiting. The accumulation or overproduction of melanin may cause skin hyperpigmentation and inhibitors of TYR are thus of interest to the cosmeceutical industry. Several TYR inhibitors are used to treat skin hyperpigmentation, however, some are ineffective and possess questionable safety profiles. This emphasises the need to develop novel TYR inhibitors with better safety and efficacy profiles. The small molecule, 3-hydroxycoumarin, has been reported to be a good potency TYR inhibitor (IC₅₀ = 2.49 µM), and based on this, a series of eight structurally related 3-hydroxyquinolin-2(1H)-one derivatives were synthesised with the aim to discover novel TYR inhibitors. The results showed that four of the derivatives inhibited TYR from the champignon mushroom Agaricus bisporus (abTYR) with IC₅₀ < 6.11 µM. The most potent inhibitor displayed an IC₅₀ value of 2.52 μM. Under the same conditions, the reference inhibitors, thiamidol and kojic acid, inhibited abTYR with IC₅₀ values of 0.130 and 26.4 μM, respectively. Based on the small molecular structures of the active 3-hydroxyquinolin-2(1H)-one inhibitors which are amenable to structure optimisation, it may be concluded that this class of compounds are good leads for the design of TYR inhibitors for cosmeceutical applications.

100 Deals associated with Dicumarol

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KEGG	Wiki	ATC	Drug Bank
D03798	Dicumarol	B01AA01	DB00266

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Indication	Country/Location	Organization	Date
Venous Thrombosis	CN	Shanghai Sine Pharmaceutical Co. Ltd.	01 Jan 1995

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