Summary:
Τhe present thesis involves the design and synthesis of new pregnenolone (PREG)
and dehydroepiandrosterone (DHEA) analogues with the aim to evaluate their
biological properties.
Especially for the pregnanolone analogues, their design was based on recent
bibliographic data concering the anticancer activity of similar derivatives. In
our case, the compounds bear modifications on the D ring of the steroid
backbone, where several arylalkynyl groups were introduced. The activity of
these novel steroids was evaluated against a series of cancer cell lines and
the compounds exhibited significant antiproliferative activities.
As for the dehydroepiandrosterone analogues, their design was based on the
neuroprotective properties of this endogenous steroid. In detail, we
synthesized 2 series of 17-spirocyclic derivatives: the first includes steroids
which bear a spiro- epoxide ring (substituted or not) at position 17 or a
substituted spiro-cyclopropyl ring at the same position, whereas the second
series comprises steroids with spiro-pyrane or furane rings at C17. The
17-spiro-epoxides protected neurons from apoptosis significantly without
exhibiting endocrine side effects, while their neuroprotective activity was
confirmed by in vivο experiments in experimental autoimmune encephalomyelitis
(EAE). Moreover, the correlation of the in vitro results with the active
conformations of the above mentioned compounds was achieved by a combination of
minimization algorithms with stochastic and systematic conformational analysis.
Finally, based on our preliminary results concerning a possible interaction of
dehydroepiandrosterone with receptors of nerve growth factor (NGF) we
synthesized a dehydroepiandrosterone analogue which was covalently attached to
NovaPEG amino-resin. Immunoprecipitation experiments revealed that the
immobilized DHEA pulls down the receptors of nerve growth factor, thus
indicating that dehydroepiandrosterone exerts its neurotrophic properties by
directly interacting with NGF.
Keywords:
Neurosteroids, Antiproliferative activity, Neuroprotection , Apoptosis, neurodegenerative diseases
