Related Experiment Video

Updated: Aug 26, 2026

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

Anti-calmodulin acridone derivatives modulate vinblastine resistance in multidrug resistant (MDR) cancer cells

Ravi Hegde1, Padma Thimmaiah, Mayur C Yerigeri

  • 1Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570006, India.

European Journal of Medicinal Chemistry
|February 28, 2004
PubMed

Insights

New acridone compounds combat multidrug resistance (MDR) in cancer chemotherapy. These novel agents enhance chemotherapy drug uptake and exhibit potent anti-MDR activity, offering a promising avenue for improved cancer treatment.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Cancer Biology

Background:

  • Multidrug resistance (MDR) significantly limits chemotherapy efficacy in cancer treatment.
  • Acridone derivatives are explored for their potential to overcome MDR.

Purpose of the Study:

  • To synthesize novel acridone analogues.
  • To evaluate their ability to reverse MDR in cancer cells.
  • To investigate the structure-activity relationship and mechanism of action.

Main Methods:

  • Synthesis of acridone parent compounds (1A, 1B) via Ullmann reaction, cyclization, and N-alkylation.
  • Nucleophilic substitution reactions to create N-(omega-Chloroalkyl) analogues (3A-13A, 3B-13B).
  • Assay of vinblastine uptake in KBChR-8-5 cells and calmodulin-dependent cyclic AMP phosphodiesterase inhibition.

Main Results:

  • Synthesized acridone analogues significantly enhanced vinblastine uptake (2.6-13.1-fold) compared to verapamil.
  • Substitution at C-4 position with -OCH3 group improved cytotoxic and anti-MDR activities.
  • A strong positive correlation was observed between anti-calmodulin activity and cytotoxicity/anti-MDR effects.

Conclusions:

  • Novel acridone analogues demonstrate significant potential in overcoming MDR.
  • Structure-activity relationship studies highlight the importance of specific substitutions for enhanced activity.
  • Inhibition of calmodulin-dependent phosphodiesterase is a key mechanism underlying the anti-MDR effects of these compounds.

Related Concept Videos

Drugs that Destabilize Microtubules01:10

Drugs that Destabilize Microtubules

Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing...
Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
Drugs that Stabilize Microtubules01:15

Drugs that Stabilize Microtubules

Microtubules are dynamic structures that undergo cycles of catastrophe and rescue. The microtubules play a central role in cell division by forming the spindle apparatus for segregating the chromosomes. This makes them ideal targets for regulating dividing cells in tumors and malignant cancer cells. Microtubule stabilizing drugs help stabilize the microtubule formation and promote its polymerization. Paclitaxel was the first microtubule stabilizing agent used as anticancer drug in chemotherapy...
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...