Rational hopping of a peptidic scaffold into non-peptidic scaffolds: structurally novel potent proteasome inhibitors derived from a natural product, belactosin A

Abstract

Rational scaffold hopping of the natural product belactosin A derivative was successfully achieved based on the pharmacophore model constructed. The peptidic scaffold was replaced by significantly simplified non-peptidic scaffolds, by which weak belactosin A (IC 50 = 1440 nM) was converted into highly potent non-peptidic inhibitors (IC 50 = 26-393 nM).In the drug discovery process, not only desired biological effect on target biomolecule, but also other various properties such as metabolic stability, membrane permeability, solubility, toxicity profile, and synthetic accessibility of leads, have to be optimized.

Natural product scaffolds as inspiration for the design and synthesis of 20S human proteasome inhibitors

“…Flexible achiral nonpeptidic analogues with a b-lactone moiety and aromatic tails were synthesized by Kawamura et al using a topology-based scaffold hopping approach. 170 These synthetically accessible inhibitors represent novel scaffolds with improved drug-likeness in comparison to past belactosin analogues. Simplified nonpeptidic belactosin scaffolds Chart 13 The belactosin inhibitors are depicted.…”

“…were further explored through synthesis of hybridized bortezomib and epoxomicin analogs. 170,171 Divergence from the b-lactone moiety of the belactosin scaffold stemmed from an interest to incorporate more stable electrophilic warheads. Nakamura et al first sought to optimize the belactosin C scaffold in 2009 through the introduction of a boronic acid moiety like that of bortezomib.…”

Exploring the Effect of Structure-Based Scaffold Hopping on the Inhibition of Coxsackievirus A24v Transduction by Pentavalent N-Acetylneuraminic Acid Conjugates

“…This is the result of, e.g., development of computational methods referred to as "scaffold hopping" [16] and the realization that the diversity of scaffolds in approved drugs are relatively low [17]. Whether the selection of a novel scaffold for an active compound is based on "scaffold hopping" methodology or on traditional structure-based reasoning [18], the general idea is to retain enough similarity for the compound to remain active, normally achieved by keeping key substituents for binding. This may result in altering the properties of the molecule or may move it into novel chemical space [15,16].…”

Scaffold-Hopping of Aurones: 2-Arylideneimidazo[1,2-a]pyridinones as Topoisomerase IIα-Inhibiting Anticancer Agents

“…10 Recently, scaffold hopping of a natural product proteasome inhibitor Belactosin A has been reported, which led to development of highly potent nonpeptidic inhibitors. 11 Toward the aim of topoisomerase II-targeting anticancer drug discovery and development, 12−14 we considered scaffoldhopping of bioactive flavonoids class of compounds. We have already discovered scaffold-hopped analogues of flavones and isoflavones, 2/3-arylpyridopyrimidinones, as Topo II-targeting anticancer agents.…”