Enantiopure bicyclic lactams: synthesis and biological evaluation

Abstract

N-Methyl-D-Aspartate (NMDA) receptors are fundamental for the normal function of the central nervous system and have an important role in memory and learning. An overactivation of these receptors results into an influx of excess of calcium cation (Ca2+) leading to neuronal loss associated with major degenerative disorders including Parkinson’s and Alzheimer’s diseases. Since the 80s, a big interest emerged of both academia and industry to develop drugs targeting the NMDA subtype of glutamate receptors with potential application for the treatment of some degenerative disorders. The main successes were amantadine (39) and memantine (40), two compounds which belong to adamantanes’s family, approved by FDA and used currently in the clinic. Another important area of therapeutic interest is cancer, which is considered the first and second causes of deaths on developed and developing countries, respectively. Statistical studies estimate that in 2030 the number of deaths caused by this disease will be 13.2 million. For this reason, it is essential the discovery of new methodologies and therapeutic agents for the treatment of cancer. The main goal of this thesis is the enantioselective synthesis of small molecules, more precisely phenylalaninol- and tryptophanol-derived bicyclic lactams, with potential application as NMDA receptor antagonists and antitumor agents, respectively. From the library of phenylalaninol derivatives, two new were promising NMDA receptor antagonists were identified. In particular, compounds 1c and 1d revealed to be more active than the hit compound, 1a, with IC50 values of 39 μM and 36 μM, respectively. Derivatives of another amino alcohol, (1S, 2R)-(−)-cis-1-amino-2-indanol, were also synthesized and a new antagonist, compound 6b, was identified with IC50 value of 51 μM. A hit-to-lead process of these three compounds was performed and the determination of respective IC50 values is in progress. For the series of tryptophanol derivatives, a hit compound (4c) was identified which revealed an IC50 value of 60 μM in MCF-7 cell lines (breast adenocarcinoma). A structural derivatization was performed, leading to five more active compounds (8b-f) with IC50 values between 6.7 and 9.0 μM, for the same cancer cell line. Furthermore, these five compounds were also evaluated in other cancer cell lines, and revealed to be selective for MCF-7 cell line, as well as non-toxic for normal cells (HEK 293)