TOTAL SYNTHESIS AND ANTITUMOR EVALUATION OF ANALOGS OF NITIDINE-CHLORIDE AND FAGARONINE-CHLORIDE (INDENOISOQUINOLINE, LEAD-TETRAACETATE, PHENYISOQUINOLINE)
Abstract
Nitidine and Fagaronine, two benzophenanthridine alkaloids, have shown antitumor activity in animal studies. Nitidine exhibits activity against L1210 and P388 mouse leukemias and is reported to have curative activity against Lewis lung carcinoma. Fagaronine is known to prolong life in mice possessing P388 leukemia. However, due to their acute toxicity, both nitidine and fagaronine have been dropped from the NCI screening program. As part of an ongoing program to synthesize potential antineoplastic agents, the synthesis and antitumor evaluation of analogs of nitidine and fagaronine was undertaken. The focal point of these syntheses has been the condensation reaction between Schiff bases and anhydrides. This has culminated in the total synthesis of five indenoisoquinolinium analogs and four phenylisoquinolinium analogs of nitidine and fagaronine. In addition, a new route to 4-phenylisoquinolinium salts was discovered. This research has also lead to the discovery of a new lead tetraacetate reaction where a carboxylic acid was shown to generate an alkyne and a tertiary alcohol in unprecedented fashion. The target compounds have shown promising antitumor activity. The indenoisoquinoline analog of nitidine, a tumor panel compound, has shown significant antitumor activity against P388 lymphocytic leukemia, L1210 lymphoid leukemia, B16 melanocarcinoma and M5076 ovarian carcinoma. The analog is also an effective inhibitor of acetylcholinesterase. The three tested indenoisoquinoline analogs of fagaronine have all displayed activity against P388 lymphocytic leukemia. The tested phenylisoquinolinium analog of nitidine was cytotoxic but totally devoid of antitumor activity. The corresponding fagaronine analog is awaiting screening. This study has shown that the indeno(1,2-c)isoquinolines, like the benzo c phenanthridines, also seem to require a flat molecular topology for antitumor activity. Methoxy substitution at the C-10 position does not hinder the antitumor activity.
Degree
Ph.D.
Subject Area
Organic chemistry
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.