Process Development of a Potent Neuroprotector Agent: Collismycin A

Abstract

An efficient synthetic process for the natural product of marine origin, collismycin type A, a potent neuroprotector agent, has been developed. This new synthetic route avoids chromatographic steps, implies an improvement cost, and provides easy access to large scale.

Synthesis and characterization of a new ditopic bipyridine-terpyridine bridging ligand using a Suzuki cross-coupling reaction

“…The 2,2′-bipyridine-4-boronic acid (5) ligand was prepared in a five-steps reaction starting with 2,2′-bipyridine and the 4′-(4-boronatophenyl)-2,2′:6′,2′′-terpyridine (9) ligand was synthesized in a four-steps reaction involving a Kröhnke reaction to prepare 1-[2-oxo-2-(2-pyridyl)ethyl]pyridinium iodide (6), 4-bromo-2′azachalcone (7), and 4′-(4-bromophenyl)-2,2′:6′,2′′-terpyridine (8). All compounds (1), 27 (2), 27 (3), 28 (4), 28 (5), 29 (6), 30 7, 31 (8), 31 and (9) 22,29, were characterized using conventional methods such as NMR and mass spectrometry. All data were consistent with the literature values (see Supplementary Material).…”

Characterization of the metallo-dependent amidohydrolases responsible for “auxiliary” leucinyl removal in the biosynthesis of 2,2′-bipyridine antibiotics

“…To confirm the metallo-dependent amidohydrolase activity of CaeD and ColD, we synthesized compounds 1 and 2 to act as substrates and compounds 3 and 4 to act as the product standards by slightly modifying the methods that were previously reported [33] ( Fig. S2 ).…”

“…The amide was formed by using l -leucine methyl ester hydrochloride as a reagent, then the methyl ester was hydrolyzed to afford TFA-bound intermediate 1 . In contrast, the synthesis of 4 was branched from intermediate 1–2 , and intermediate 2–5 was prepared from 1 – 2 by a four-step sequence that is known to introduce a methylthio moiety at C5 [33] . In a second sequence of reactions, the new aldehyde group of 2 – 5 was oxidized to carboxyl by NaClO 2 , and the methoxy group at position C4 was hydrolyzed in aqueous hydrobromic acid to give compound 4 .…”

“…These syntheses were performed according to a slightly modified version of a method that was previously described [33] ( Fig. S2a ).…”

Strategies to diversify natural products for drug discovery

“…Salas and co‐workers confirmed that collismycin A ( 64 , a 2,2‐bypiridine molecule with antimicrobial, cytotoxic, and anti‐inflammatory activities) biosynthesis in Streptomyces sp. was regulated through two pathway‐specific regulators in which ClmR1 negatively regulated production, whereas ClmR2 positively controlled the expression of most genes in the collismycin A gene cluster .…”