Total synthesis of Gombamide A and Actinophenanthroline A. Discovery, optimization and characterization of novel positive allosteric modulators for the metabotropic glutamate receptor subtype 1

Abstract

The first total synthesis of Gombamide A, a cyclic thiopeptide from the sponge Clathria gombawuiensis, is reported. The convergent synthesis features a disulfide bond forming cascade to close the 17-membered macrocycle and a selenoazidylation procedure to access the unusual para-hydroxystyrlyamide moiety. The synthesis required 11 steps, in its longest linear sequence, and proceeded in 9% overall yield.

The first total synthesis of Actinophenanthroline A, an alkaloid from a marine actinobacterium with an unprecedented 1,7-phenanthroline core, has been achieved. The route highlights of the protecting group-free synthesis feature two regioselective nitrosylation/reduction sequences and a Brønsted acid-catalyzed Doebner-Miller reaction. The synthesis required only six linear steps and proceeded in 24% overall yield.

The metabotropic glutamate receptor type 1 (mGlu1) has been implicated in several neural processes. Moreover, recent genetic studies showed that mutations in the GRM1 gene are enriched in patients with schizophrenia, and we confirmed that a subset of these mutations decreased receptor response; suggesting that therapies targeting the receptor’s function recovery might be beneficial in these patients. Suitable chemical tools to activate the receptor and perform target validation studies are needed to test this hypothesis. First efforts in the development of novel mGlu1 positive allosteric modulators (PAM) started by repurposing a known mGlu4 PAM chemotype through a multidimensional iterative parallel synthesis approach and lead to the discovery of VU0483605, a novel, selective and submicromolar mGlu1 PAM. After several iterations, the more potent and plasma stable VU0486321 was discovered. Finally, efforts have been made towards the optimization of VU0486321 pharmacokinetic profile in order to increase its half-life. This campaign led to the discovery of VU6004909, an analog with a fluoro substitution that confers great selectivity for mGlu1 and VU0487351, an isoindolinone analog, with excellent plasma stability. Overall, these new compounds represent potent and selective chemical tools, with good CNS penetration and a balanced DMPK profile. We expect that these new probes will allow the exploration of the role of mGlu1 in schizophrenia and other neuropsychiatric disorders.