Design of Coibamide A Mimetics with Improved Cellular Bioactivity

Abstract

Coibamide A, a cyclic depsipeptide isolated from a Panamanian marine cyanobacterium, shows potent cytotoxic activity via the inhibition of the Sec61 translocon. We designed a coibamide A mimetic in which the ester linkage between MeThr and d -MeAla in coibamide A was replaced with an alkyl linker to provide a stable macrocyclic scaffold possessing a MeLys(Me) residue. Taking advantage of a facile solid-phase synthetic approach, an structure–activity relationship (SAR) study of the newly designed macrocyclic structure was performed, with a focus on altering the pattern of N -methyl substitution and amino acid configurations. Overall, the simplified macrocyclic scaffold with an alkyl linker resulted in a significantly reduced cytotoxicity. Instead, more potent coibamide A derivatives with a β-(4-biphenylyl)alanine (Bph) group were identified after the optimization of the Tyr(Me) position in the original macrocyclic scaffold of coibamide A based on the characteristic apratoxin A substructures. The similar SAR between coibamide A and apratoxin A suggests that the binding site of the Tyr(Me) side chain at the luminal end of Sec61α may be shared.

Marine natural products

“…112 Total syntheses of bastimolides A and B, 113,114 and the 10-aza-9oxakalkitoxin analogue of kalkitoxin 115 were reported in 2022. Other notable work on cyanobacterial NPs included a report on the biosynthesis of the carbon skeleton of nocuolin, 116 synthesis of coibamide A mimetics with improved cellular bioactivity, 117 and an evaluation of antitrypanosomal activity of gallinamide and analogues. As has been the case in previous years, the genus Aspergillus was overwhelmingly the most common source of fungal metabolites this year.…”

Design of Synthetic Surrogates for the Macrolactone Linker Motif in Coibamide A

“…20 We also previously investigated modification of the CbA macrolactone substructure. 21 CbA mimetic 2a, in which the D-MeAla 11 -MeThr 5 moiety at the ring junction was substituted with a simple MeLys(Me) (Figure 1B), displayed moderate cytotoxic activity. 21 This lysine-linked CbA mimetic was applicable to our lead optimization campaign, in which we revealed that substitution of Tyr(Me) 10 in CbA with (biphenylyl)alanine (Bph) led to a significant increase in cytotoxic potential.…”

“…Yao et al reported an SAR study which demonstrated that the potent cytotoxic activity of CbA was maintained when the two N , O -dimethylserines [MeSer­(Me)] in CbA were replaced with N -methylalanines (MeAla), whereas most derivatives with simplified structures were less potent (Figure A) . We also previously investigated modification of the CbA macrolactone substructure . CbA mimetic 2a , in which the d -MeAla 11 -MeThr 5 moiety at the ring junction was substituted with a simple MeLys­(Me) (Figure B), displayed moderate cytotoxic activity .…”

“…21 CbA mimetic 2a, in which the D-MeAla 11 -MeThr 5 moiety at the ring junction was substituted with a simple MeLys(Me) (Figure 1B), displayed moderate cytotoxic activity. 21 This lysine-linked CbA mimetic was applicable to our lead optimization campaign, in which we revealed that substitution of Tyr(Me) 10 in CbA with (biphenylyl)alanine (Bph) led to a significant increase in cytotoxic potential. The modifications of CbA with MeLys(Me) facilitated the synthesis of a series of derivatives to avoid possible racemization and less efficient couplings.…”

“…Next, we synthesized CbA derivatives 3a,b by Fmoc-based SPPS using Fmoc/Alloc protected lysine derivatives 4a,b , according to the synthetic procedure for CbA mimetics in our previous study ( Scheme S2 ). 21 The bioactivity profile of the resulting peptides 3a,b was investigated by using a standard MTS antiproliferative/cell viability assay to assess the cytotoxic potential of CbA analogues against human A549 lung cancer cells ( Table 1 ). Peptide 3a , with a 3,6-dimethyllysine moiety at the ring junction, showed enhanced cytotoxic activity compared to that of nonmethylated peptide 2a [CC 50 ( 3a ) = 41 nM].…”