DESIGN OF NOVEL NUCLEAR SUBSTITUTED STYRYL KETONES. EVALUATION FOR ANTITUMOR, CYTOTOXIC AND ANTIMICROBIAL ACTIVITIES
Date
1978-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Degree Level
Doctoral
Abstract
The preparation, mass spectral properties, antineo-plastic, antimicrobial and other pharmacological properties of 1-(hydroxypheny1)-1-nonen-3-ones and related 0-benzoyl esters, 0-ethers and Mannich bases are presented. The effect of a Mannich base on the incorporation of labelled precursors into certain biopolymers is outlined.
Mass spectral data, spectra and fragmentation pat-terns of the compounds prepared are given. Of particular interest are the fragmentation patterns of l-(orthosubsti.-tuted phenyl)-1-nonen-3-ones which showed the dependence of the formation of the benzopyrylium ion on the leaving group abilities of the ortho-substituent as well as the stabilities of the resultant benzopyrylium ions.
The alkaline hydrolysis of the p-substituted benzoyl esters of 1-(hydroxypheny1)-1-nonen-3-ones was undertaken in order to seek a correlation between the rate of hydrolysis of the esters and the in vivo P388 lymphocytic leukemia screening data. All the esters were inactive and hence a clearcut cor-relation was not possible.
The esters showed the expected increase of the second order rate constant as the acyl substituents became more elec-tron withdrawing. This increase in the second order rate con-stant was more pronounced in the p-substituted befizoyl esters of 1-(2-hydroxypheny1)-1-nonen-3-one probably because of the more effective destabilisation of the crowded transition
state. This series of esters had a rho value of 2.43 and the esters of 1-(4-hydroxypheny1)-1-nonen-3-one had a rho value of 1.84. The alkaline hydrolysis of p-substituted phenyl benzoates was undertaken in order to determine the p value of
0
II
-CH==CHCC613'
which was found to be +0.25. The rho value of this series of esters was 1.65.
The 1-(alkoxyphenyl)-1-nonen-3-ones showed signifi-cantly higher activities against P388 lymphocytic leukemia cells in vivo. Since the ethers do not hydrolyse in basic media, the ethers may be able to reach the target site. The claim has been made that the fluid around some cancer cell systems is more acidic than the fluid surrounding normal tis-sue cells, and thus the ethers may preferentially hydrolyse to the corresponding active phenol close to the cancer cells. The water soluble Mannich bases of the l-(hydroxyphenyl)-1-nonen-3-ones showed slightly higher activities compared to the parent compounds. With the exception of the Mannich bases, all the compounds screened were non-toxic at the high-est dose used (200 mg/kg).
1-(Hydroxypheny1)-1-nonen-3-ones and the, related Mannich bases showed significant activities. In addition, the Mannich bases showed marked antihistaminic, analgesic and anti-inflammatory effects.
The effects of (E)-4-dimethylaminomethy1-1-(3,4-dichloropheny1)-1-nonen-3-one (NC97) on L1210 lymphoid leu-kemia cells in vitro is described. The incorporation of deoxythymidine and deoxyuridine into DNA was inhibited to the extent of 84-90% and 20-29% respectively at the 1-5/pg/m1 dose. This effect is opposite to that exhibited by the clin-ically used alkylating agents chlorambucil and cyclophospha-mide. The incorporation of uridine into RNA was inhibited by 49-66%, while the incorporation of leucine into protein was inhibited 71-79% at the 1-5/pg/m1 dose.
Description
Keywords
Mannich bases, lymphoid leukemia cells
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Chemistry and Chemical Engineering