Column Chromatography-Free Solution-Phase Synthesis of a Natural Piper-Amide-like Compound Library

Abstract

We have achieved an efficient solution-phase parallel synthesis of a library of natural piper-amide-like compounds from the bifunctional β-phosphono-N-hydroxy-succinimidyl ester intermediate. The primary important feature in our study is the construction of natural-product-like molecules through the adaptation of sophisticated organic reactions that create water-soluble byproducts for a chromatography-free purification. This simple and efficient method rapidly provides a combinatorial library of high yield and purity. The library was evaluated against GPCR targets to demonstrate its potential use as a tool for drug discovery and in chemical biology.

A novel synthetic Piper amide derivative NED‐180 inhibits hyperpigmentation by activating the PI3K and ERK pathways and by regulating Ca2+ influx via TRPM1 channels

“…The compound, NED-180, was chosen as the lead candidate with the highest inhibition of melanin production and tyrosinase activity with no apparent cytotoxicity for cultured melan-a cells (Data S1 and S2). The active compound, NED-180, was resynthesized on a larger scale, purified by silica gel column chromatography, and fully characterized to confirm the structure as described previously (Kim et al, 2013). The chemical and spectroscopic data are as follows: light yellow solid, MP 86-89°C, 1 34.9, 64.3, 64.4, 109.9, 113.5, 117.2 (2C), 119.9, 125.8 (2C), 127.7 (2C), 131.9, 141.9, 141.8, 142.0, 143.5, 153.4 Melan-a cells and normal human epidermal melanocytes (NHEM) were stained with L-DOPA, which detects in situ tyrosinase activity and is a more sensitive indicator of changes in melanin synthesis than the determination of total melanin levels.…”

“…This group of natural products exhibits diverse and versatile biological activities, including stimulation of melanocyte proliferation and differentiation (Venkatasamy et al., ). Given their interesting and versatile biological activities of natural piper amides, we had previously constructed a natural product‐like compound library embedded with the common structural motif of natural piper amides (Kim et al., ). In an attempt to find novel depigmenting agents, we screened this compound library.…”

A natural piper-amide-like compound NED-135 exhibits a potent inhibitory effect on the invasive breast cancer cells

“…We have previously constructed a library of piper amide-like compounds from the bifunctional b-phosphono-N-hydroxysuccinimidyl ester without chromatographic purification [26]. The 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) mediated coupling reaction and an Horner-Wadsworth-Emmons type reaction provided the desired a,b-unsaturated amide.…”

“…In an attempt to discover new lead compounds for the treatment of breast cancer through inhibiting MMP-9 expression and invasion/migration, we screened our piper amide-like compound library [26]. We evaluated the inhibitory activities of randomly selected library members against S1P-induced MMP-9 expression and investigated the effects of these compounds on breast cell invasion.…”

NED416, a novel synthetic Sirt1 activator, promotes cutaneous wound healing via the MAPK/Rho pathway

“…A piper amide derivative, NEd416, was synthesized according to a previously reported method (28), purified by silica gel column chromatography and characterized. The spectral data obtained were consistent with previously reported values (29 Cell treatment.…”