PRODRUGS OF ENONES AS CANDIDATE ANTICANCER AGENTS
Date
1992
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Degree Level
Doctoral
Abstract
Cancer chemotherapy commonly cures some rare
tumours but only very rarely cures common tumours. The major
reason for this is that the majority of the anticancer drugs
available have no particular specificity towards tumour cells
and their effect is due to their action on proliferating
cells in the cell cycle. Hence there is a need for more
effective and selective anticancer drugs.
Alkylating agents provide approximately half
of the clinically useful anticancer drugs in the treatment
of cancer. a,[3-Unsaturated ketones and related derivatives are
known to possess alkylating potential which has been
associated with their biological properties. Therefore this
group of compounds can be classified as biological alkylators
and hence fall into the category of the alkylating agents.
The present investigation was based on the
following observations. First, certain a,(3-unsaturated 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.
Hence these compounds may be free from undesired carcinogenic
and mutagenic properties associated with clinically used
anticancer agents. Second, certain oximes of a,(3-unsaturated
ketones had greater activity towards P388 leukemia in mice
than the precursor enones. Since it is also known that some
of the tumour cells are more acidic than the corresponding
normal cells, oximes may undergo hydrolysis and selective
release of ketones in tumourous tissue may occur.
The objectives of the present investigation
are the design, synthesis and cytotoxic evaluation of the
following series of compounds.
(i) Mannich bases of cycloalkanones which may undergo
deamination to release the potentially cytotoxic
a,(3-unsaturated ketones. These include mono- and
bis- Mannich bases.
(ii) Oximes of Mannich bases as prodrugs were
contemplated with a view to attain selective
release of the ketones in the tumourous tissue.
(iii) Benzoates as pro-prodrugs were proposed since
oximes have a polar hydroxy group which may impede
passage via membranes and also in the case of in
vivo •experiments they may be metabolized readily
e.g., by forming .-glucuronides. The oxime
benzoates may permit the esters to reach the sites
of action.
(iv) A number of mono- and bis- substituted
arylidenecycloalkanones and their oximes, oxime
benzoates and related compounds were also suggested
for the same reasons as outlined in (i)-(iii).
Of the Mannich bases of cycloalkanones, the
bis-derivatives were found to be more active than the
corresponding mono-derivatives. In the L1210 screen the bis-
Mannich bases of cyclopentanone and cycloheptanone were found
to be more active than the corresponding cyclohexanone
derivative. However the activity decreased with further
increases in the size of the cycloalkane ring. Most of the
Mannich bases screened by the NCI against various human
tumour cell lines in vitro showed specificity towards
leukemia cells. Compounds IIa, Iib, IIIc and IIId were found
to be selectively effective against colorectal cancer when
screened against human colon cell lines in vitro.
Mannich bases of cyclohexanone with different
amino functions having varying pka values were synthesized.
However no correlation between the basicity of the amino
function and cytotoxicity was found. Acyclic analogs of mono-
and his- Mannich bases of cycloalkanones did not show any
clear correlation between rigidity/flexibility and
cytoxicity.
Various oximes were synthesized successfully
as prodrugs. These compounds were found to be inactive except
XVIII.
Benzoates were synthesized as pro-prodrugs,
but these compounds were found to be devoid of any
cytotoxicity in the L1210 and the NCI in vitro screens.
A number of mono- and bis (arylidene) -
cycloalkanones were synthesized and evaluated in various
screens. Among both the mono- and Jois- derivatives, compounds
having substituents with positive sigma values were found to
be the most active.
Oximes of jnono- substituted arylidene
cyclohexanones and 2-benzylidenecyclopentanone were
synthesized and were found to be inactive in both the L1210
and the NCI in vitro screens. While attempting to prepare the
oxime of 2,6-bis(benzylidene)cyclohexanone, a different
compound i.e. XXXa was obtained whose structure was deduced
by 300 MHz 1H spectroscopy and confirmed by X-ray analysis.
/
HC
--11(; )
HORN
N--OH
XXXa
H
/
A series of analogs of XXXa were synthesized
and evaluated against EMT6 cells. These compounds were shown
to be weakly active in this screen. However in the NCI in
vitro screen against various human cell lines, these
compounds showed similar toxicity as melphalan in general.
Compound XXXI was prepared, which like XXVIIa
contains part of the XXXa molecule and may indicate the
pharmacophoric group of XXXa. But compounds XXVIIa and XXXI
were shown to be inactive towards EMT6 cells.
Oxime benzoates of mono(arylidene)cyclo-
alkanones were found to be inactive in the the L1210 and NCI
in vitro screens.
Since a number of compounds containing the
carbimino (C=N) group are often more susceptible to
hydrolysis under acidic conditions, hydrazones of mono- and
bis(arylidene)cyclohexanones were prepared. The hydrazone of
his(benzylidene)cyclohexanone showed greater activity than
the parent ketone whereas the corresponding phenylhydrazone
was inactive, while the phenylhydrazone of
mono(benzylidene)cyclohexanone was found to be more active
than the parent ketone. The thiosemicarbazone of 2-
benzylidenecyclohexanone was found to be more active than the
parent ketone and the corresponding semicarbazone.
Description
Keywords
Prodrugs, Enones, Anticancer
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Pharmacy and Nutrition
Program
Pharmacy