MANNICH BASES OF CYCLOALKANONES AND RELATED COMPOUNDS AS CYTOTOXIC AGENTS
Date
1994
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Degree Level
Masters
Abstract
Cancer chemotherapy is primarily limited by the non-selective action of drugs and hence toxicity to normal cells. Therefore one of the most important features of new drugs should be selectivity towards tumor cells.
Mannich bases have been found to possess some degree of selective antineoplastic activity. These compounds demonstrate a greater affinity for the thiol groups than amino and hydroxy functions in biomolecules. Hence carcinogenic and mutagenic side effects may be avoided.
The aim of the present investigation was to design and prepare a number of Mannich bases which could be screened against P388-D1 leukemia cells and also in the NCI screen. Thus the following series of compounds were designed and synthesized:
• Mono Mannich bases of cycloalkanones which are potentially cytotoxic through conversion to the corresponding a,ß-unsaturated ketones.
• Bis Mannich bases of cycloalkanones. These were designed to examine the theory of sequential cytotoxicity.
• Quaternary ammonium salts of mono and bis Mannich bases with a view to attain a faster rate of deamination and hence greater cytotoxicity than the corresponding tertiary amines.
• 2-(Arylmethylene)cycloalkanones and the corresponding Mannich bases.
The Mannich bases of cyclopentanone and cyclohexanone generally demonstrated significant cytotoxicity against P388-D1 leukemia cells. However the activity is decreased with further increases in the size of the cycloalkanering. Thus the cyclododecanone mono and bis Mannich bases were in general far less active.
The bis Mannich bases of cyclohexanone were found to be more cytotoxic in the P388-D1 screen than the corresponding mono derivatives.
In order to investigate whether there is a correlation between the cytotoxicity and the basicity of the amino function and hence the rate of deamination, various series of mono and bis Mannich bases of cyclopentanone, cyclohexanone and cyclododecanone with different amino moieties having varying log Kb values were synthesized and evaluated. However, no correlation was observed between the predicted rates of deamination and cytotoxicity.
A number of mono and bis Mannich bases of cycloalkanones synthesized in this project showed greater cytotoxicity and selectivity than melphalan in the NCI screen.
2-(Arylmethylene)cycloalkanone Mannich bases demonstrated greater cytotoxicity against P388-D1 leukemia cells than the corresponding 2-(aryl-methylene)cycloalkanones. The activities of the Mannich bases in which the aryl ring was unsubstituted or contained a 4-methyl group were similar to that of melphalan.
Description
Keywords
MANNICH BASES, CYTOTOXIC AGENTS
Citation
Degree
Master of Science (M.Sc.)
Department
Medicinal Chemistry