Author: Panigrahi, Sanjali S. ; Ronning, Donald R. ; Mahto, Sohan ; Mahato, Ram I. ; Jayasinghe, Yahani P. ; Staller, Dalton W. ; Dong, Yuxiang ; Kumar, Virender

Background and Aims:Chronic liver disease leads to ~2 million deaths annually. Cyclic AMP (cAMP) signaling has long been studied in liver injury, particularly in the regulation of fatty acid (FA) β-oxidation and pro-inflammatory polarization of tissue-resident lymphocytes. Phosphodiesterase 4B inhibition has been explored as a therapeutic modality, but these drugs have had limited success and are known to cause significant adverse effects. The PDE4 inhibitor 2-(4-([2-(5-Chlorothiophen-2-yl)-5-ethyl-6-methylpyrimidin-4-yl]amino)phenyl)acetic acid) (known as A-33) has yet to be explored for the treatment of metabolic diseases.Approach and Results:Herein, we evaluated the efficacy of A-33 in the treatment of animal models of alcohol-associated liver disease and steatotic liver disease. We demonstrated that A-33 effectively ameliorated the signs and symptoms of chronic liver disease, resulting in significant decreases in serum alanine aminotransferase and aspartate aminotransferase levels, decreased overall fat and collagen deposition in the liver, decreased intrahepatic triglyceride concentrations, and normalized expression of genes related to β-oxidation of fatty acids, inflammation, and extracellular matrix deposition. We also designed and synthesized a novel analog of A-33, termed MDL3, which inhibited both phosphodiesterase 4B and PDE5A and was more effective in ameliorating pathophysiological signs and symptoms of liver injury and inflammation. In addition, MDL3 re-sensitized obese mice to glucose and significantly inhibited the pathological remodeling of adipose tissue, which was not observed with A-33 administration.Conclusions:In conclusion, we synthesized and demonstrated that MDL3, a novel phosphodiesterase 4B and PDE5A inhibitor, presents a promising avenue of exploration for treating chronic liver disease.

01 Feb 2025·Bioorganic & Medicinal Chemistry

Discovery of novel xanthohumol C derivatives regulating XRCC2 transcription and expression for the treatment of colorectal cancer

Article

Author: Hu, Yina ; Wang, Kun ; Wang, Dalong ; Zheng, Xiaohui ; Li, Bin ; Cao, Di ; Zhu, Qianqian ; Wang, Yan ; Liu, Zhiguo ; Shi, Changgui ; Zheng, Jiahao ; Wang, Mengying

X-ray repair cross-complementing 2 (XRCC2), a critical protein in homologous recombination (HR), plays a significant role in the occurrence, progression, and drug resistance of colorectal cancer (CRC). In this study, a series of xanthohumol C derivatives were synthesized, and their anticancer activity was evaluated. The results revealed that A33 demonstrated the potent anticancer activity and effectively inhibited the proliferation of CRC cells in vitro. Mechanistic investigations revealed that A33 suppressed the transcription and expression of XRCC2, resulting in cell cycle delay and the accumulation of DNA damage, ultimately leading to cell proliferation inhibition. Furthermore, A33 displayed high safety, favorable bioavailability (F = 37.51 %), and potent tumor growth inhibition in vivo, which highlighting its potential as a candidate for the development of novel anti-CRC therapies.

01 Dec 2024·European Journal of Medicinal Chemistry

Novel 2-aminothiazole analogues both as polymyxin E synergist and antimicrobial agent against multidrug-resistant Gram-positive bacteria

Article

Author: Chen, Yuce ; Chen, Daijie ; Li, Zhen ; Lin, Ting ; Li, Zhong ; Xu, Xiaoyong

The widespread emergence of antibiotic resistance poses a substantial challenge to global health. While polymyxin E serves as a final option in treatment, its effectiveness is hindered by dose-related toxicity. A crucial strategy for addressing this issue involves incorporating an antibiotic adjuvant to enhance the antibiotic's efficacy and decrease the required dosage. Here, we reported a multifunctional antibacterial compound A33, containing a 2-aminothiazole scaffold. In vitro studies demonstrated that A33 in combination with polymyxin E inhibited the growth of various Gram-negative bacteria, meanwhile with minimum inhibitory concentrations (MICs) of 0.5-4 μg/mL against twenty-three Gram-positive bacteria, including two drug-resistant strains. In vivo studies showed significant efficacy of the combined treatment of A33 and polymyxin E in a mouse infection model. The mice treated with compound A33 (64 mg/kg) and polymyxin E (0.5 mg/kg) in combination had a 100 % survival rate. Mechanistic studies suggested that A33 might exert its synergistic effect by targeting the outer membrane of Gram-negative bacteria. The ADMET data demonstrated that A33 possessed good pharmacokinetic profiles and drug-likeness properties. Overall, the optimized compound A33 assisted polymyxin E in combating various Gram-negative bacteria and exhibited bactericidal effects against drug-resistant Gram-positive bacteria, offering a new potential therapeutic approach for managing mixed bacterial infections.

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Indication	Highest Phase	Country/Location	Organization	Date
Mild cognitive disorder	Discovery	United States	State University of New York at Buffalo	31 Mar 2015

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