Seven compounds, named β-sitosterol (1), daucosterol (2), (+)-pinoresinol-β-D-glucoside (3), (-)-syringaresinol 4-O-β-D-apiofuranosyl-(1→2)- β-D-glucopyranoside (4), 4-hydroxybenzoic acid (5), 2-(3', 4'-dihydroxyphenyl)-1, 3-pepper ring-5-aldehyde (6) and spinosin (7) were isolated from the rhizome of Acorus calamus var. angustatus Besser. 3, 4, 6 and 7 were isolated from this medicinal plant for the first time. Structures were elucidated by physicochemical properties and extensive spectroscopic analysis, as well as by comparison with literature data. The anti-inflammatory activity and related mechanisms of the seven compounds showed that compounds 1-7 all increased the levels of GSH-PX and SOD and decreased the levels of MDA, TNF-α, IL-1β and IL-6. Compound 4 showed the best effect of anti-inflammatory and Beclin-1 inhibition. These results suggest that compound 4 has stronger anti-inflammatory effect and provide preliminary evidence that the mechanism of action of compound 4 in attenuating LPS-induced inflammatory damage may be related to the inhibition of Beclin-1-dependent autophagy.

08 Aug 2024·ACS Medicinal Chemistry Letters

AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications

Article

Author: Frydenvang, Karla ; Oliaro-Bosso, Simonetta ; Vigato, Chiara ; Pignochino, Ymera ; Giordano, Giorgia ; Lolli, Marco L ; Salladini, Edoardo ; Zonari, Daniele ; Tucciarello, Cristina ; Hussain, Samrina ; Boschi, Donatella ; Mirza, Osman Asghar ; Pippione, Agnese C ; Truong, Ha H ; Vanzetti, Gaia ; Henriksen, Niel M

AKR1C3 is an upregulated enzyme in prostate and other cancers; in addition to regulating hormone synthesis, this enzyme is thought to play a role in the aggressiveness of tumors and in the defense against drugs. We here used an unbiased method to discover new potent AKR1C3 inhibitors: through an AI-based virtual drug screen, compound 4 was identified as a potent and selective enzymatic inhibitor able to translate this activity into a pronounced antiproliferative effect in the 22RV1 prostate cancer cell model. As other known AKR1C3 inhibitors, compound 4 determined a significantly increased activity of abiraterone, a drug approved for advanced prostate cancer. Compound 4 also showed a synergic effect with doxorubicin in osteosarcoma cell lines; specifically, the effect is correlated with AKR1C3 expression. In this research work, therefore, the use of AI allowed the identification of a new structure as an AKR1C3 inhibitor and its potential to enhance the effect of chemotherapeutics.

01 Jun 2024·Phytochemistry

Anti-pancreatic cancer activity of cassane diterpenoids isolated from the seeds of Caesalpinia sappan mediated by autophagy activation via ROS/AMPK/mTORC1 pathway

Article

Author: Wang, De-Sheng ; Liu, Yu-Yao ; Wu, Yun ; Wu, Xing-De ; Qi, Yan-Yan ; Yan, Run-Cheng ; Ma, Ke ; Li, Yong-Jiao ; Chen, Ya ; Wang, Qi-Qi ; Hu, Guo-Xian ; Su, Jia ; Ding, Lin-Fen ; Hu, Ming

Three undescribed cassane diterpenoids, caesalpanins D-F (1-3), and seven known ones were isolated from the seeds of Caesalpinia sappan. Structures and absolute configurations of 1-3 were elucidated based on the extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and ECD calculations. Structurally, compound 1 was the first example of 18-norcassane diterpenoid and 2 was a rare 20-norcassane diterpenoid having an unusual five-membered oxygen bridge between C-10/C-18. The anti-proliferative activity of 1, 3, and 4-10 against PANC-1 cells (pancreatic ductal adenocarcinoma cell line) was evaluated, and phanginin H (4) was found to exhibit anti-cancer activity with IC₅₀ value of 18.13 ± 0.63 μM. Compound 4 inhibited PANC-1 cell growth by arresting the cell cycle at G2/M phase via regulation of cyclin-dependent kinases, and the self-renewal and metastasis of PANC-1 cells by suppressing cancer cell stemness. Furthermore, compound 4 induced ROS generation and subsequently activated autophagy, which was demonstrated by the formation of autophagic vacuoles and dynamic change of autophagic flux. The induced ROS accumulation resulted in AMPK activation and subsequently regulation of mTORC1 activity and ULK phosphorylation, indicating that 4 triggered autophagy through ROS/AMPK/mTORC1 pathway. These findings suggested that 4 might potentially be an autophagy inducer for the therapy of pancreatic cancer.

100 Deals associated with 17β-HSD5 inhibitors(University of Turin)

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Indication	Highest Phase	Country/Location	Organization	Date
Osteosarcoma	Preclinical	Italy	University of Turin	03 Jul 2024
Prostatic Cancer	Preclinical	Italy	University of Turin	03 Jul 2024

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