Bisbenzylisoquinoline alkaloids and P-glycoprotein function: A structure activity relationship study.

Area of Science:

• Pharmacology
• Biochemistry
• Medicinal Chemistry

Background:

• P-glycoprotein overexpression in cancer cells leads to multidrug resistance by extruding anticancer drugs.
• Bisbenzylisoquinoline alkaloids are known to modulate P-glycoprotein function and reverse this resistance.

Purpose of the Study:

• To investigate the structure-activity relationship of various bisbenzylisoquinoline alkaloids on P-glycoprotein function.
• To compare the inhibitory effects of specific alkaloids on P-glycoprotein in daunorubicin-resistant leukemia cells.

Main Methods:

• Utilized daunorubicin-resistant leukemia MOLT-4 cells to assess P-glycoprotein inhibition.
• Compared the effects of tetrandrine, isotetrandrine, fangchinoline, berbamine, dauricine, cepharanthine, and armepavine.

Main Results:

• Tetrandrine showed the strongest P-glycoprotein inhibitory effect, followed by fangchinoline and cepharanthine.
• Berbamine and isotetrandrine had moderate effects, while dauricine and armepavine showed minimal influence.
• The 18-membered ring structure and specific 3D stereochemistry of bisbenzylisoquinoline alkaloids are essential for P-glycoprotein inhibitory activity.

Conclusions:

• The 18-membered ring and double isoquinoline units connected by oxygen bridges are indispensable for P-glycoprotein inhibitory activity.
• Stereo-configuration significantly impacts the inhibitory potency, suggesting 3D structure is more predictive than 2D for P-glycoprotein inhibition.
• These findings offer insights into P-glycoprotein binding pocket specificity and guide the development of novel multidrug resistance reversal agents.