Synthesis and biological evaluation of diaryl ether linked DC-81 conjugates as potential antitumor agents.

Abstract

A series of new diaryl ether linked pyrrolobenzodiazepine (PBD) conjugates (4a-i, 5a-i and 6a-f) was synthesized and evaluated for their anticancer activity against a panel of 11 human cancer cell lines. These conjugates exhibited significant anticancer activity with GI50 values in the range of 0.1-3.88 μM. Some of the potent conjugates (4b, 4h, 5h, 6b, 6c and 6e) were further investigated on cell cycle distribution. FACS analysis showed the accumulation of cells in G0 phase indicating the apoptosis inducing nature of these conjugates. Moreover, compound 6b caused a decrease in the mitochondrial membrane potential, which indicates the apoptotic nature of the compound through mitochondrial mediated pathway. Further conjugates 4b, 4h and 6b induce the activation of caspase and PARP proteins, followed by apoptotic cell death in MCF7 cell line.

• Authors: Ahmed Kamal, A Viswanath, M Janaki Ramaiah, J N S R C Murty, Farheen Sultana, E Vijaya Bharathi, G Ramakrishna, Pranjal Sarma, A Lavanya, S N C V L Pushpavalli, Manika Pal Bhadra
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 13 Issue 10 Pg. 1590-600 (Dec 2013) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 23438825 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Ethers
• Pyrroles
• pyrrolo(2,1-c)(1,4)benzodiazepine
• Benzodiazepines
• Poly(ADP-ribose) Polymerases
• Caspase 3

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Benzodiazepines (chemical synthesis, pharmacology)
• Caspase 3 (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Epithelial Cells (drug effects, metabolism, pathology)
• Ethers
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Inhibitory Concentration 50
• Mammary Glands, Human (drug effects, metabolism, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism)
• Molecular Structure
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Pyrroles (chemical synthesis, pharmacology)
• Resting Phase, Cell Cycle (drug effects)
• Signal Transduction
• Structure-Activity Relationship