Foto del docente

Vincenzo Tumiatti

Full Professor

Department for Life Quality Studies

Academic discipline: CHIM/08 Pharmaceutical Chemistry

Director of Single Cycle Degree in Pharmacy


Keywords: Alzheimer's disease polyamines drug design medicinal chemistry anticancer agents multipotent agents

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.