Summary:
This thesis is concerned with the design of new compounds, based on the results
of
the antiproliferative action of compounds previously prepared in our
laboratory(Msc
dissertation).
The encouraging pharmacologic results of the compounds that we have synthesized
in
the past led to the design of the compounds presented in this thesis, which is
based on
the length of the chain. linking the aromatic ring with the aminic nitrogen of
the
phenylalkylamine skeleton, which remotes affinity for sigma receptors; this is
enhanced by the adamantane hydrophobic moiety.
Based on the above mentioned rationale the following categories of compounds
were
synthesized:
1. 5-(1-Adamantyl)-5,5-diphenylpentylamines (1) and 6-(1-Adamantyl) 6,6-
diphenylhexylamines (2)
2. 4-[α-(1-Adamantyl)benzyl]benzylamines 3(n=1)
3. 4-[α-(1-Adamantyl)benzyl]phenethylamines 3(n=2)
4. γ-{4-[α-(1-Adamantyl)benzyl]phenyl}propylamines 3(n=3)
5. δ-{4-[α-(1-Adamantyl)benzyl]phenyl}butilamines 3(n=4)
6. 4-(2-Adamantyl)anilines 4(n=0)
7. 4-(2-Adamantyl)benzylamines 4(n=1)
8. 4-(2-Adamantyl)phenethylamines 4(n=2)
9. γ-[4-(2-Adamantyl)phenyl]propylamines 4(n=3).
The Pharmacological screening of derivatives 1, 2 and 3 indicates a noticeable
antiproliferative action.
The comparison of the antiproliferative actions of derivatives 1 and 2 with the
derivatives III, synthesized in the past, reveals that the elongation of the
carbon chain
from 4 atoms (derivatives III) to 5 (derivatives 1) and 6 (derivatives 2) does
not alter
significantly the pharmaceutical profile.
As far as derivatives 3 is concerned, it is intriguing that γ-
phenylpropylamines 3(n=3)
show better activity than their congeners 3(n=1). Derivatives 3(n=2) and 3(n=4)
exhibit weaker action than both derivatives 3(n=3) and 3(n=1). In conclusion
when
the distance between the aromatic ring and the cationic aminic nitrogen is three
carbon atoms, the antiproliferative activity is optimum.
Comparison between derivatives 3(n=3) and derivatives I, synthesized in the
past,
leads to the conclusion that derivatives 3(n=3) are more effective. Remarkable
is the
fact that both derivatives 3(n=3) and I bear a three carbon chain, 1 Nitrogen
atom and
2 Carbon atoms for derivatives I and 3 atoms of Carbon in the case of
derivatives
3(n=3).
This far, the results from the binding studies of the new compounds with sigma
receptors are limited and refer only to derivatives 3(n=3)a and c. This do not
allow
for any reliable conclusions to be drawn. However, it seems that these
derivatives
behave as mixed σ1/σ2 ligands.
Last, in vivo studies of the anticancer activity of the derivative 3(n=3)a in
the
pancreatic cancer cell line BX-PC3 demonstrated high cytotoxicity against this
type
of cancer, which is at least three times higher than that of 5-fluorouracil.
The pharmacologic screening for the C2-adamantane derivatives 4 is still in
progress.
Keywords:
ω-(1-Adamantyl)-ω, ω, -diphenylkylamines, 4-[α-(10Adamantyl)benzyl]phenylkylamines, Antiproliferative activity, Affinity with sigma receptors, In vivo anticancer activity
