ABSTRACT
Chemistry that allows selective modification of the carboxylic acid groups of the squalene synthase inhibitor zaragozic acid A (1) was developed and applied to the synthesis of compounds modified at the 3-,4-,5-,3,4-,3,5-, and 4,5-positions. A key step in this procedure is the selective debenzylation by transfer hydrogenolysis in the presence of other olefinic groups. These compounds were tested in the rat squalene synthase assay and in vivo mouse model. Modification at C3 retains significant enzyme potency and enhances oral activity, indicating that C3 is not essential for squalene synthase activity. Modification at C4 and C5 results in significant loss in enzyme activity. In contrast, substitution at C3 or C4 enhances in vivo activity. Furthermore, disubstitution at the C3 and C4 positions results in additive in vivo potency.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic , Bridged Bicyclo Compounds/chemistry , Carboxylic Acids/chemistry , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Tricarboxylic Acids/chemistry , Animals , Bridged Bicyclo Compounds/pharmacology , Esterification , Male , Mice , Microsomes, Liver/enzymology , Molecular Structure , Rats , Structure-Activity Relationship , Tricarboxylic Acids/pharmacologyABSTRACT
This debate examines the arguments for and against the proposal that surgical excision alone is adequate treatment for primary colorectal cancer. The arguments in favour are that the results from curative surgery are excellent and that despite many trials of adjuvant chemotherapy, radiotherapy and immunotherapy, the proposed benefits remain unproven. Recent improvements in surgical technique, particularly for dissection of rectal tumours, have shown the way towards further improvement using surgery alone, and it is clear from a national survey that technical factors related to individual surgeons play a large part in determining recurrence rates. With optimum primary treatment, surgical excision alone is indeed adequate therapy. The arguments against this motion are that although a considerable number of patients do survive with surgery, the 5-year survival rate is poor when there is extensive local invasion or lymphatic metastases. Surgery starts therapy by reducing the tumour load, but other modalities are required to destroy the cells which might subsequently develop into metastases. Trial results with adjuvant therapy are encouraging, although many contain too few patients. We cannot be content with the results of treatment of Dukes' Stage B and C tumours; more trials are needed to determine the best treatment for these patients.
