Design, Synthesis, and Biological Evaluation of Hybrid Glypromate Analogues Using 2-Azanorbornane as a Prolyl and Pipecolyl Surrogate

Abstract

Neurodegenerative disorders of the central nervous system are a class of heterogeneous pathologies affecting millions of people worldwide and represent a global health burden in developed and developing countries. Without restorative treatments currently available, research on neuroprotective drugs is considered a health priority. In this study, new analogues of the glycyl-Lprolyl-L-glutamic acid (Glypromate) neuropeptide were designed, synthesized, and biologically evaluated using (1R,3S,4S)-2azanorbornane-3-carboxylic acid as a hybrid construct of L-proline and L-pipecolic acid. Neuroprotection assays carried out in human neuroblastoma SH-SY5Y cells using 6-hydroxydopamine as a stress inducer showed great percentage of recovery (29.7−40.0%) at 100 μM. Among this series, [(1R,3S,4S)-2-glycyl-2-azanorbornane-3-carbonyl]-L-aspartic acid (2a) stands out with a remarkable percentage of recovery (40.0%, at 100 μM) and safe toxicological profile in SH-SY5Y and human adipose mesenchymal stem cells.

Concise Overview of Glypromate Neuropeptide Research: From Chemistry to Pharmacological Applications in Neurosciences

“…. These compounds did not exhibit meaningful cytotoxicity in SH-SY5Y and human adipose mesenchymal stem cells up to 100 μM . Moreover, the neuroprotective activity of hybrid Glypromate analogs 41 – 44 was assessed in SH-SY5Y cells using 6-OHDA as a neurotoxic insult .…”

“…Recently, the chemical conjugation of Glypromate dimethyl ester (60) with lipoic acid and peracetylated L/D configuration-DOPA was shown to be a prolific strategy to explore synergistic effects, affording conjugates 80 and 81, respectively.…”

“…Sampaio-Dias and co-workers described the design and preparation of constrained analogs of Glypromate based on (1R,3S,4S)-2-azanorbornane-3-carboxylic acid (a hybrid construct of L-proline and L-pipecolic acid and also a structural isomer of b 7 Pro) as shown in Figure 5. 60 These bicyclic Glypromate analogs (41−44, Figure 5) were successfully synthesized using the one-pot method previously described (section 2.3.2.). 46 These compounds did not exhibit meaningful cytotoxicity in SH-SY5Y and human adipose mesenchymal stem cells up to 100 μM.…”

“…46 These compounds did not exhibit meaningful cytotoxicity in SH-SY5Y and human adipose mesenchymal stem cells up to 100 μM. 60 Moreover, the neuroprotective activity of hybrid Glypromate analogs 41−44 was assessed in SH-SY5Y cells using 6-OHDA as a neurotoxic insult. 60 All compounds of this series exhibited a significant (p < 0.01) increase in the recovery values after 6-OHDA injury, ranging between 24.7 and 40.0% at 100 μM, while the parent neuropeptide demonstrated a 12.8% recovery tendency (p = 0.0611) at the same concentration.…”

A formal (3+2) cycloaddition strategy toward 2-azanorbornanes

“…[11][12][13] Given the promising biological activity of 2-azanorbornane containing molecules, a complementary approach relying on photochemistry at reduced temperatures and with greater substitutional flexibility would enable the increased study and adoption of the core in biological applications. [14][15][16][17] We envisioned that the ring-opening of a protected N-cyclopropyl amine with an intramolecular alkene tether could initiate a cascade radical cyclization sequence to furnish a 2azanorbornane in analogy to our previously reported methods. 20…”