Structural Simplification of Bioactive Natural Products with Multicomponent Synthesis. 3. Fused Uracil-Containing Heterocycles as Novel Topoisomerase-Targeting Agents

Abstract

After the initial discovery of antiproliferative and apoptosis-inducing properties of a camptothecin-inspired pentacycle based on 1H-indeno[2’,1’:5,6]dihydropyrido[2,3-d]pyrimidine scaffold, a library of its analogues as well as their oxidized planar counterparts were prepared utilizing a practical multicomponent synthetic protocol. The synthesized compounds exhibited submicromolar to low micromolar antiproliferative potencies toward a panel of human cancer cell lines. Biochemical experiments are consistent with the dihydropyridine library members undergoing intracellular oxidation to the corresponding planar pyridines, which then inhibit topoisomerase II activity leading to inhibition of proliferation and cell death. Because of facile synthetic preparation and promising antitopoisomerase activity, both the dihydropyridine and planar pyridine-based compounds represent a convenient starting point for anticancer drug discovery.

Anticancer Properties of an Important Drug Lead Podophyllotoxin Can Be Efficiently Mimicked by Diverse Heterocyclic Scaffolds Accessible via One-Step Synthesis

“…5a,b Further work revealed, however, that low nanomolar potencies are predominantly associated with compounds containing the unsubstituted pyrazole moiety (R=H, Table 1). Synthesis of such compounds involved combining 5-aminopyrazole, tetronic acid and an aromatic aldehyde in ethanol and refluxing these reaction mixtures for 0.5–3 hours.…”

“…5 We recently described a dihydropyridopyrazole scaffold designed on the basis of a potent anticancer cyclolignan, podophyllotoxin, and readily prepared by combining an aminopyrazole, tetronic acid and an aromatic or heteroaromatic aldehyde in a one-pot condensation process (Figure 1). 5a,b …”

Unprecedented C-2 arylation of indole with diazonium salts: Syntheses of 2,3-disubstituted indoles and their antimicrobial activity

“…23 HeLa testing was also accomplished according to a previously published method. 24 b Methicillin-resistant S. aureus c Susceptible S. aureus strain d Low-level vancomycin-resistant Enterococcus e The data are presented as GI 50 ± SD from four experiments. f ND = not determined …”

Structural simplification of bioactive natural products with multicomponent synthesis. 4. 4H-Pyrano-[2,3-b]naphthoquinones with anticancer activity

“…1 To address this challenge we have advocated the utilization of natural product-mimetic scaffolds, which can be synthetically accessed in one step by utilizing multicomponent reactions (MCR). 2 for example, we showed that the stereochemically complex structure of an important anticancer lead podophyllotoxin can be efficiently simplified to fused dihydropyridine scaffolds, efficiently prepared with MCRs. 2a–c Compounds based on this heterocyclic scaffold retain the antitubulin mode of action of the natural product and rival podophyllotoxin in their antiproliferative potency and apoptosis inducing potential.…”

“…2 for example, we showed that the stereochemically complex structure of an important anticancer lead podophyllotoxin can be efficiently simplified to fused dihydropyridine scaffolds, efficiently prepared with MCRs. 2a–c Compounds based on this heterocyclic scaffold retain the antitubulin mode of action of the natural product and rival podophyllotoxin in their antiproliferative potency and apoptosis inducing potential. Other successful applications of this approach involve the discovery of pyranoquinolones, designed to be mimetics of pyranoquinolone alkaloids, 2d,e and topoisomerase-targeting indenopyridines inspired by the structure of camptothecin.…”