Organocatalytic Asymmetric Synthesis of Spiro-oxindole Piperidine Derivatives That Reduce Cancer Cell Proliferation by Inhibiting MDM2–p53 Interaction

Abstract

Asymmetric synthesis of pharmacologically interesting piperidine-fused spiro-oxindole derivatives has been achieved via an organocatalytic Michael/aza-Henry/hemiaminalization cascade reaction. Chiral compounds synthesized by this strategy potently inhibited the proliferation of several breast cancer cell lines. Mechanistic studies suggest that the most potent compound 9e can directly interfere with MDM2-p53 interactions and elevate protein levels of p53 and p21, thereby inducing cell cycle arrest and mitochondrial apoptosis.

Design, synthesis and molecular mechanisms of novel dual inhibitors of heat shock protein 90/phosphoinositide 3-kinase alpha (Hsp90/PI3Kα) against cutaneous melanoma

“…In order to assess the possibility of subroutine cell death underlying 8m treatment, flow cytometry with annexinV/PI dual staining was used to assess the activation of apoptosis [39][40][41][42][43][44][45] . Hoechst 33258 staining also clearly showed that nuclear morphological changes in apoptotic cells, including chromatin condensation and apoptotic bodies, mediated apoptosis ( Figure 5(D)).…”

Protecting‐Group‐Free Synthesis of 3‐Amino‐3‐α‐prenyl‐oxindoles through the Direct Prenylation of Isatin‐Derived Imines

“…Since spirooxindoles bearing a nitrogen heterocycle at the C3‐position form the basic skeleton of many natural products and therapeutic agents, and they are generally more effective at inhibiting cancer cell proliferation than oxygen‐ or sulfur‐containing heterocyclic C3‐substituted molecules, we believe that the preparation of their analogs would be useful for structure‐activity relationship studies. Therefore, we randomly chose several N ‐unprotected and N ‐protected 3‐amino‐3‐prenyl‐2‐oxindoles 2 for the synthesis of spirooxindoles containing a five‐membered nitrogen heterocycle to further investigate the synthetic utility of this protocol.…”

Facile synthesis of two azete-steroid derivatives and theoretical evaluation of its interaction with the aromatase enzyme

“…Infrared spectra (IR) were evaluated using i50 FT-IR Nicolet spectrometer. 1 H and 13 C NMR (nuclear magnetic resonance) spectra were determinate with a Varian VXR300/5 FT NMR spectrometer at 300 MHz (megahertz) in CDCl 3 (deuterated chloroform). EIMS (electron impact mass spectroscopy) spectra were evaluated using a Finnigan Trace Gas Chromatography Polaris Q-Spectrometer.…”

“…It is noteworthy that some drugs have been used to treatment of breast cancer such as tamoxifen (estrogen-receptor antagonist) [5], anastrozole, letrozole or exemestane (aromatase inhibitors) [6][7][8], fisetin or methyl paraben (17-hydroxy dehydrogenase type 1 inhibitors) [9,10]; however, some of these drugs may produce some adverse effects such as secondary endometrial cancer [11] and bone loss [12]. In the search of new pharmacological treatment to breast cancer, some drugs have been developed; for example, the asymmetric synthesis of a piperidine derivative via an organocatalytic Michael-Henry reaction with biological activity against breast cancer in vitro [13]. In addition, a study showed the preparation of nimesulide from 2-Amino-5-nitro-phenol as a breast cancer inhibitor using SK-BR-3 cells [14].…”