Chemistry Reference
In-Depth Information
1.
The ratio of compounds to descriptors should be > 5.
2.
The descriptors should not be intercorrelated (interdescriptor correlation coefficient should be less than <
0.5).
CHOLINE KINASE
The rational design of novel antiproliferative and antitumour strategies is based on the recognition of novel
intracellular targets for the modifications produced by the activity of different oncogenes and the changes in tumour
suppressor genes [19].
The development of human cancer is thought to be the result of mutations in multiple genes that control normal cell
proliferation, differentiation and apoptosis. Genes that are often found mutated in malignancies are referred to as
proto-oncogenes. Activation of these proto-oncogenes to oncogenes and/or the loss of function of tumour suppressor
genes may cause deranged intracellular signalling. The
ras
gene encodes 21-kDa proteins, which play an important
role in signal transduction. One of the most commonly altered gene products in human solid tumours includes Ras
proteins. Ras mutations, which are found in approximately 30% of all human malignancies, lead to an increase in
cell proliferation and tumour formation [20].
Choline kinase (ChoK), a cytosolic enzyme presents in various tissues, catalyses the phosphorylation of choline to
form phosphorylcholine (
P
Cho). Choline is not synthesized by the cells and either a high-affinity transport system in
nerve terminals, or an ubiquitous low-affinity transport system is responsible for its uptake. Free choline can also be
generated from phosphatidylcoholine (PC) by phopholipase D (PLD), an enzyme that is regulated by growth factors
and activated by oncogenes. More recently, PC hydrolysis has been implicated in cell signalling. PC is the most
abundant phospholipid in eukaryotic cell membranes and is hydrolyzed by phophatidylcholine-specific
phospholipase D (PC-PLD) to give choline and phosphatidic acid (PA).
ChoK has recently gained attention as a relevant component in signalling pathways involved in the regulation of cell
growth. This latter function was noticed by the discovery of elevated levels of
P
Cho in cells transformed by
ras
oncogenes. Finally, some carcinogens, such as polycyclic aromatic hydrocarbons and 1,2-dimethylhydrazine,
induced rat liver and colon cancers with increased ChoK activity, further supporting the possible role of ChoK in
cancer generation.
The analysis of the inhibition of the structures was tested using a purified ChoK preparation from yeast as a target.
This assay allows us to evaluate the effect on compound activities without considering the possible passage through
membranes.
The antiproliferative assays was carried out on the HT-29 cell line. This cell line was established from a colon
adenocarcinoma, one of the most frequent solid cancers in humans that is also mainly resistant to chemotherapy,
making these cells appropriate for the search of new antitumour drugs.
The substituents at position 4 of the pyridinium moiety were electron-releasing, neutral or electron-withdrawing
groups (negative values of
R
denote the electron-donating character and positive value, the electron-withdrawing
character of the substituent). To start with, the selection of the substituents to be introduced in position 4 of the
pyridinium nucleus was dictated by criteria of minimum effort and maximum informative content. Following this
line, the smallest number was chosen from easily synthetically accessible compounds which could give the
maximum spread and orthogonality of the main physicochemical properties,
i.e.
, the electronic and hydrophobic
ones. From the results obtained it is clear that the presence of electron-withdrawing groups (-COOH,
5
and -CN,
6
)
leads to inactive compounds as ChoK inhibitors.
Table
2
shows the structure, biological results and clog
P
values for compounds
1-10
. clog
P
values were calculated
by using the Ghose-Crippen modified atomic contribution system (ATOMIC5 option) of the PALLAS 2.0
programme [21].
