Function-Oriented Synthesis: Design, Synthesis, and Evaluation of Highly Simplified Bryostatin Analogues

Abstract

Using a function-oriented synthesis strategy, we designed, synthesized, and evaluated the simplest bryostatin 1 analogues reported to date, in which bryostatin’s A- and B-rings are replaced by a glutarate linker. These analogues, one without and one with a C26-methyl group, exhibit remarkably different protein kinase C (PKC) isoform affinities. The former exhibited bryostatin-like binding to several PKC isoforms with K i’s < 5 nM, while the latter exhibited PKC affinities that were up to ∼180-fold less potent. The analogue with bryostatin-like PKC affinities also exhibited bryostatin-like PKC translocation kinetics in vitro, indicating rapid cell permeation and engagement of its PKC target. This study exemplifies the power of function-oriented synthesis in reducing structural complexity by activity-informed design, thus enhancing synthetic accessibility, while still maintaining function (biological activity), collectively providing new leads for addressing the growing list of therapeutic indications exhibited by PKC modulators.

Marine natural products

“…620 A function-oriented synthetic study has resulted in the preparation of the most simplied and synthetically accessible bryostatin 1 analogue known to date, with potency and protein kinase C (PKC) translocation activity comparable to that displayed by bryostatin 1. 621 Bryostatin 1 has been shown to both increase synaptic density and decrease immature dendritic spine density in cortical cell cultures, which may be the basis for its promise as an agent for treating Alzheimer's disease. 622 Relevant review articles on bryozoans published in the past year include one which summarises chemoecological data on bryozoans and potential biomedical applications, 623 and two which focus on bryostatin synthesis and drug applications, 624,625 with the latter one focusing on preclinical and clinical research.…”

Steglich esterification: A versatile synthetic approach toward the synthesis of natural products, their analogues/derivatives

“…But they have achieved only the synthesis of bryostatin analogues so far which behave similar to bryostatin and are more active biologically. The synthesis of bryostatin analogue, reported by Wender et al in 2020, commenced from neopentyl glycol 276 which was converted to compound 277 over a few steps [ 99 ]. Next, the compound 277 underwent deprotection followed by Steglich esterification with monobenzyl glutarate in the presence of DCC and DMAP to give ester 278 .…”

β-Lactams from the Ocean

“…Indeed, the impressive list of antitumor-antibiotic structures isolated from marine sources (didemnin, gephromycin, gliotoxin, grincamycin, ilimaquinone, lamellarin, largazole, lurbinectedin, meridianin, peloruside, phorbazole, plinabulin, staurosporine, trodusquemine, withanolide…) exemplifies both unique chemical structure and exceptional biological activity [ 5 , 6 , 7 ]. While the experience with another marine antitumor antibiotic (bryostatin) has underscored the extraordinary difficulty of translating exceptional in vitro activity to clinical relevance [ 8 , 9 , 10 ], it has also proven that marine-derived structures are “privileged” in that their structural diversification can uncover new clinical utilities [ 11 , 12 ]. Given that the future for antibacterial discovery is structured to counter infections caused by multi-drug-resistant bacteria, chemical entities that have privilege are prized.…”