A new class of natural products with a unique ring system was identified with hepatoprotective activity and the for use in the control of liver disease and its progression to cancer or cirrhosis.


Technology: MUSC inventors have identified a new class of natural compounds with a unique ring system that possess hepatoprotective activity for use in control of liver disease such as cancer or cirrhosis, and liver damage induced by toxins. Kadsuraol A-C (compounds 1-3), are three highly modified tetrahydrocyclobutaphenanthrofuranone-type lignans with a new carbon skeleton comprising a four-membered ring across C-1′–C-8’ and isolated from the roots of Kadsura longipedunculata. Compounds 1-3 were evaluated for in vitro hepatoprotective activity against N-acetyl-p-aminophenol (APAP)-induced toxicity in HepG2 (human hepatocellular liver carcinoma cell line) cells, using the liver protectant bicyclol as a positive control. Treating the cells with Compound 3 resulted in a survival rate of 48.22%, which is similar to bicyclol (48.77%). Through these findings the inventors identified a structure-activity relationship and that the nature of the C-7 chain is crucial for the hepatoprotective activity, which is likely associated with the length and/or the size of compound 3. Further, compounds 1-3 did not show activity in a differential cytotoxicity zone assay used for measure toxicity in vitro which includes 11 tumor cells (data not shown), indicating that compound 3 is a non-cytotoxic hepatoprotective molecule.

Overview: Chronic liver disease caused by xenobiotics and viral infection leads to liver cancer; the second most common cancer in the world. Hepatitis B and hepatitis C infections exacerbates liver cancer condition. In 2018, WHO reported that around 788,000 people die from primary liver cancer every year. It is also reported that from 1999 to 2015, deaths from liver cancer in the US increased by 60% while deaths from other cancers decreased by 26%. An effective approach to chronic liver disease control is chemoprevention, which can help improve abnormal liver function and inhibit hepatitis replication. Several antiviral drugs such as lamivudine, adefovir, dipivoxil, and entecavir have been successfully used to treat chronic hepatitis B (HBV) or chronic hepatitis C (HCV) infections. However, the therapeutic efficacy of these drugs is still limited and have severe side effects. Dibenzocyclooctadiene lignans are the primary hepatoprotective active ingredients of Schisandra chinensis and Kadsura longipedunculata which are known as “liver tonic” in Asian Herbal Medicine for chronic liver disease and poor liver function. Inventors at MUSC have identified three unique tetrahydrocyclobutaphenanthro-furanone-type lignans containing a four-membered ring across C-1′–C-8’ and their absolute configurations were defined by a combination of computational approaches. Importantly, compound 3 showed non-cytotoxic hepatoprotective effects against APAP-induced toxicity in HepG2 cells comparable to a clinically used control.


Applications: Kadsuraol compound 3 could be used a hepatoprotective agent for hepatitis B and hepatitis C viral infections and liver cancer.

Advantages: Kadsuraol compound 3 is simultaneously less cytotoxic and more cell protective for hepatic cells.

Key Words: Kadsuraol, Liver cancer, hepatoprotective, tetrahydrocyclobutaphenanthro-furanone-type lignans, hepatitis B, hepatitis C, APAP, acetometophin toxicity, liver disease


Related Publications:


Wang, Xiaojuan, et al. "The Computationally Assisted Assignment of the Kadsuraols, a New Class of Chemopreventive Agents for the Control of Liver Cancer ". Org Lett. 2018 Sep 21;20(18):5559-5563.


Inventors:      Mark T. Hamann, Xiaojuan Wang.

Patent Status:                     Provisional filed

MUSC-FRD Technology ID:       P1875


Patent Information:
For Information, Contact:
MUSC Foundation for Research Development
Mark Hamann
Xiaojuan Wang
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