ABSTRACT
Hypoxia-inducible factor (HIF)-1α is a crucial transcription factor associated with cancer metabolism and is regarded as a potent anticancer therapeutic strategy within the hypoxic microenvironment of cancer. In this study, stilbenoid derivatives were designed, synthesized, and assessed for their capacity to inhibit HIF-1α-associated cancer metabolism and evaluated for inhibition of cancer cell viability and HIF activation. Through the structure-activity relationship studies, compound 28e was identified as the most potent derivative. Specifically, under the hypoxic condition, 28e reduced the accumulation of HIF-1α protein and the expression of its target genes related to glucose metabolism without affecting the expression of HIF-1α mRNA. Furthermore, 28e inhibited glucose uptake, glycolytic metabolism, and mitochondrial respiration, decreasing cellular ATP production under hypoxic conditions. In addition, 28e displayed significant anti-tumor effects and effectively suppressed the accumulation of HIF-1α protein in tumor tissue in vivo xenograft model. These findings suggest that our stilbenoid derivatives exert their anticancer effects by targeting HIF-1α-centered cancer metabolism under hypoxic conditions.
Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit , Mice, Nude , Stilbenes , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Humans , Animals , Stilbenes/pharmacology , Cell Line, Tumor , Xenograft Model Antitumor Assays , Mice, Inbred BALB C , Structure-Activity Relationship , Cell Hypoxia/drug effects , Mice , Cell Survival/drug effects , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Antineoplastic Agents/pharmacology , Glycolysis/drug effects , Glucose/metabolismABSTRACT
A temperature-dependent cascade of reactions between tryptamines and propargylic alcohols was developed to achieve selective formation of pyrroloindoline and pyrrolo[1,2-a]indole heterocycles by Ca(II) catalysis. The cascade consists of electrophilic addition of allene at the C3 carbon of indole followed by intramolecular cyclization at 60 °C to yield pyrroloindolines. Furthermore, simultaneous 1,2-allene migration and pyrrolidine ring opening were followed by intramolecular cyclization via C-N bond formation at reflux temperature to obtain pyrrolo[1,2-a]indole scaffolds. A wide range of substrates, a clean reaction profile, scalability, and good to excellent yields are the advantages of this protocol.
