SYNTHESIS OF THIOL -DEPLETING AGENTS WITH SELECTIVE TOXICITY TO MALIGNANT CELLS
Date
1991-11
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Degree Level
Doctoral
Abstract
The present investigation was based on the following two observations. First, derivatives of styryl ketones and their corresponding Mannich bases have been found to possess antineoplastic activity with little or no affinity for the amino or hydroxyl groups found in nucleic acids. In particular the Mannich bases have a pronounced predilection for thiols and react approximately 240 times faster than the corresponding ketones. Hence these compounds may be free from undesired mutagenic and carcinogenic properties associated with present day alkylating agents. Second, L-histidinol which is a structural analog of the essential amino acid histidine has been found to protect normal cells from insult caused by various antineoplastic agents e.g. BCNU(N,N-bis-(2-chloroethyl)-N-nitrosourea), cyclophosphamide, cis-platinum etc..
The aim of the present investigation was twofold and can be oulined as follows. It starts with the synthesis of a vicompound(55a) which contains a Mannich base(a cytotoxic species) and L-histidinol. The Mannich base is a y-piperidone with two arylidene groups attached to the piperidine ring adjacent to the carbonyl function. Second, the design, synthesis and antineoplastic evaluation of some potential alkylating species(A) was contemplated with a view to developing structure-activity relationships and of obtaining a compound with optimum activity.
Description
Keywords
Mannich bases
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Pharmacy