Novel Indole-Containing Hybrids Derived from Millepachine: Synthesis, Biological Evaluation and Antitumor Mechanism Study

Abstract

Millepachine, a bioactive natural product isolated from the seeds of Millettia pachycarpa, is reported to display potential antitumor activity. In this study, novel indole-containing hybrids derived from millepachine were designed, synthesized and evaluated for their antitumor activities. Among all the compounds, compound 14b exhibited the most potent cytotoxic activity against five kinds of human cancer cell lines, with IC50 values ranging from 0.022 to 0.074 μM, making it almost 100 times more active than millepachine. Valuable structure–activity relationships (SARs) were obtained. Furthermore, the mechanism studies showed that compound 14b induced cell-cycle arrest at the G2/M phase by inhibiting tubulin polymerization and further induced cell apoptosis through reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) collapse. In addition, the low cytotoxicity toward normal human cells and equivalent sensitivity towards drug-resistant cells of compound 14b highlighted its potential for the development of antitumor drugs.

Natural compound chaetocin induced DNA damage and apoptosis through reactive oxygen species‐dependent pathways in A549 lung cancer cells and in vitro evaluations

“…This investigation results underline the importance of chaetocin in lung cancer control. The basal ROS accumulation level is higher than normal counterparts and more vulnerable to A549 cells [17, 37]. This study reports a significant level of ROS increases and mitochondrial membrane damage‐induced cell apoptosis.…”

Revolutionizing Indole Synthesis: A Microwave‐Powered Approach

“…Compounds derived from indole have gained considerable attention for their biological and pharmaceutical activities. [6,7] Indole plays a pivotal role in diverse biochemical reactions within the body, influencing aspects of bacterial physiology such as spore formation, plasmid stability, drug resistance, biofilm formation, and virulence. [8] Indole scaffolds are prevalent in crucial synthetic drug molecules, offering a reliable pathway for creating effective targets and binding to multiple receptors with high affinity, thus facilitating the development of new biologically active compounds.…”

“…This nitrogen‐based heterocycle holds notable significance in the development of heterocyclic scaffolds. Compounds derived from indole have gained considerable attention for their biological and pharmaceutical activities [6,7] . Indole plays a pivotal role in diverse biochemical reactions within the body, influencing aspects of bacterial physiology such as spore formation, plasmid stability, drug resistance, biofilm formation, and virulence [8] …”

Indole Derivatives: Unveiling New Frontiers in Medicinal and Synthetic Organic Chemistry

“…SAR was determined, and mechanistic investigations revealed that compound A caused cell-cycle arrest, specifically at the G2/M phase, inhibited tubulin polymerization, and induced cell apoptosis by accumulating reactive oxygen species and collapsing mitochondrial membrane potential. Importantly, compound A exhibited low toxicity to normal cells and showed effectiveness against drug-resistant cells, suggesting its potential for developing antitumor drugs [ 10 ]. The research primarily focused on Hypsizygus marmoreus ( H. marmoreus ) and explored its indole compounds and other bioactive constituents.…”

“…Researchers conducted a study to discover new bioactive compounds by combining molecules with biological properties to produce indole derivatives. Ten (10) derivatives were synthesized, featuring different moieties at the C-3 position. The compounds were characterized for their antibacterial, antioxidant, and fungicidal activities.…”