1- Drug Design and synthesis of derivatives (based on polyamines
scaffold) able to discriminate between the different receptors
subtypes and/or enzymes, following the concept of the
"universal template approach"
2- Drug design and synthesis of derivatives for the therapy of
Alzheimer's disease
3- Drug design and synthesis of anticancer agents
Drugs hitting a single target may be inadequate for the
treatment of diseases like neurodegenerative syndromes, diabetes,
cardiovascular diseases, and cancer, which involve multiple
pathogenic factors. Different pharmacological approaches offer
possible ways of overcoming the problems that arise from the use of
such drugs: a multiple-medication therapy (MMT) also referred to as
a “cocktail” or “combination of drugs”, a multiple-compound
medication, also referred to as a “single-pill drug combination”
(MCM), and finally, a third strategy is now emerging on the basis
of the assumption that a single compound may be able to hit
multiple targets (MTDL). Clearly, therapy besed on the use
of MTDL would have inherent advantages over MMT or MCM. In
fact it would obviate the challenge of administering multiple
single-drug entities, which could have different bioavailability,
pharmacokinetics, and metabolism. The design and synthesis of
new MTDLs was applied to discover new compounds useful for the
treatment of Alzheimer's disease and cancer.
a) Design and synthesis of new multiple targets compounds for
the treatment of Alzheimer's disease.
Alzheimer's disease (AD), the most common form of dementia in
adults, is a neurodegenerative disorder characterized by loss of
cognitive ability and severe behavioral abnormalities, and it
ultimately results in total degradation of intellectual and mental
activities. Much effort is devoted to elucidate the relationships
among the hallmarks of the disease, that is, amyloid plaques,
neurofibrillary tangles, and loss of neurons in the hippocampus and
nucleus basalis of Maynart. AD is characterized by a pronounced
degradation of the cholinergic system and by alteration in other
neurotransmitter systems as glutamatergic and serotoninergic ones.
The actual therapeutic approaches are based on different
morphological and biochemical characteristics of AD and focused on
the following directions: (i) restoring of the native levels of the
cholinergic transmission in CNS; (ii) decreasing the production or
aggregation of b-amyloid peptide (Ab), the major component of the
senile plaques, or increasing its removal; (iii) protection of
nerve cells from toxic metabolites formed in neurodegenerative
processes; (iv) activation of other neurotransmitter systems to
compensate indirectly the cholinergic function deficit. To date,
only acetylcholinesterase (AChE) inhibitors, such as tacrine,
donepezil, rivastigmine, and galantamine, and an NMDA receptor
antagonist, memantine, are available for AD treatment. These drugs
have been approved for the symptomatic treatment of AD as they do
not even address the etiology of the disease for which are used.
Some experimental evidence suggests that AChE plays also a
noncholinergic function in the development of AD. In particular,
its consistent presence in senile plaques could represent the cause
of Ab aggregation and deposition. It accelerates the assembly of Ab
into insoluble fibrils containing both Ab and AChE, which are more
toxic to cells than Ab alone. Several studies, carried out in the
presence of either competitive or noncompetitive inhibitors of AChE
to determine the molecular domain of AChE involved in the
interaction with Ab, suggest that the catalytic site of AChE does
not participate in the interaction with Ab. A potential locus of
interaction between Ab and AChE has been identified by crystal
structure data on the external surface in proximity of the
catalytic gorge of AChE and called the “AChE peripheral site”. The
specific role of AChE in amyloid formation is confirmed by
observations on butyrylcholinesterase (BChE). BChE shares many
structural and physicochemical properties with AChE and has been
detected in senile plaques and in neurofibrillary tangles, where it
is colocalized with the Ab. However, BChE does not bear a
peripheral site and does not enhance the assembly of Ab into
amyloid fibrils. It derives that compounds able to bind
simultaneously to both the catalytic and peripheral sites of AChE
should implicate advantages over inhibitors that act only on the
catalytic site because the inhibition of the peripheral binding
site might prevent the aggregation of Ab induced by AChE. On these
bases several MTDLs were synthesized in order to hit several
peculiar targets of AD.
b) Design and synthesis of new multiple targets compounds for
cancer treatment.
The discovery of new compounds endowed with selective anticancer
activity has become one of the most important goals in medicinal
chemistry. Cell proliferation has essential roles in carcinogenesis
including the process of initiation and promotion. In the
last years, thanks to the advances in understanding the mechanism
involved in malignant transformation, several important molecules
and biological pathways playing a crucial role in tumor growth have
been identified, allowing the design of new therapeutic agents. Several small molecules able to interact with important biological targets were designed and some of them based on the chemical structure of natutral products.
c) Design and synthesis of new polyamines for the biological
characterization of different receptors and/or enzymatic systems.
For a long time, the mean research line was based in the research
of selective muscarinic receptor ligands by applying the ‘universal
template approach'. According to this approach, it was hypothesized
that a polymethylene tetraamine backbone may represent a universal
template on which suitable pharmacophores can be inserted to
achieve selectivity for any given receptor or enzymatic system. The
application of this concept has allowed us, for instance, to design
polyamines displaying high affinity and selectivity for muscarinic
M2 receptors, which was achieved by introducing appropriate
pharmacophores on the polyamine backbone of methoctramine
(1), a well-known selective muscarinic M2 receptor
subtypes antagonist. The polyamine backbone, thanks to its
flexibility, may assume many low-energy conformations in an aqueous
environment. To reduce the conformational freedom of the
polymethylene chain and to determine whether flexibility is an
important determinant of potency with respect to muscarinic
receptors, some more rigid analogues of 1 were
designed and synthesized in which the inner octamethylene chain was
incorporated partially or totally into a more constrained moiety.
Finally, the application of this approach allowed us to discover
new selective ligands for different biological systems as
nicotinic, and adrenergic ones.
