Enzyme Inhibition VI: Inhibition of Reverse Transcriptase Activity by Protoberberine Alkaloids and Structure–Activity Relationships

□ Protoberberine alkaloids such as palmatine (I), 13-meth- ylpalmatine iodide (II), 2,3-methylenedioxy-10,ll-dimethoxy-13- methylprotoberberine iodide (III), 2,3-methylenedioxy-9,10-dime- thoxy-13-methylprotoberberine chloride (IV), and berberine (V) showed inhibition of reverse transcriptase activity of RNA tumor viruses in the presence of polyriboadenylic acid-oligodeoxythymidylic acid (VI), polydeoxyadenylic acid-oligodeoxythymidylic acid (VII), activated calf thymus deoxyribonucleic acid (IX), and 70S ribonucleic acid (X), but not in the presence of polyribocytidylic acid-oligodeoxyguanylic acid (VIII). These results indicated that the alkaloids caused inhibition of the enzyme activity by interacting with the template primer, particularly of the adenine-thymine base pair. Furthermore, the alkaloids competed with the template primer-binding site of the enzyme. The time course inhibition indicated that the alkaloids stopped the DNA synthesis instantly when added after the initiation of polymerization processes. Inhibition of reverse transcriptase activity was correlated with the structure and antileukemic activity of the protoberberine alkaloids.