Cytotoxic responses to aromatic ring and configurational variations in alpha-conidendrin, podophyllotoxin, and sikkimotoxin derivatives.

Abstract

Derivatives of alpha-conidendrin, podophyllotoxin, and sikkimotoxin were prepared to evaluate the cytotoxic contributions of C-4 configuration and pendant and fused arene substitutions. Dimethyl-alpha-conidendryl alcohol (5), 9-deoxypodophyllol (6), and 9-deoxysikkimol (17) were dehydrated to their respective oxolane derivatives 4, 3, and 9. Diols 5 and 6 were converted via oxabicyclo[3.2.1]octanols 10 and 14 to target oxolanes 8 and 7 where C-4 had been inverted relative to that in 3 and 4. Cytotoxicities of the five oxolanes were determined in two drug-sensitive human leukemia and two multidrug-resistant cell lines expressing P-glycoprotein or multidrug-resistance associated protein (MRP). Changing the pendant arene configuration or replacing a m-methoxy by hydrogen resulted in a 100-fold cytotoxicity loss. Replacing a methylenedioxy group in the fused arene by two methoxy substituents reduced cytotoxicity by 10-fold. Drug-resistant cell lines were equally resistant to compounds 3, 4, 8, and 9 indicating that these four compounds do not serve as substrates of the transport proteins P-glycoprotein and MRP.

• Authors: A Dantzig, R T LaLonde, F Ramdayal, R L Shepard, K Yanai, M Zhang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 44 Issue 2 Pg. 180-5 (Jan 18 2001) ISSN: 0022-2623 [Print] United States
• PMID: 11170627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Lignans
• Multidrug Resistance-Associated Proteins
• Tetrahydronaphthalenes
• conidendrin
• Podophyllotoxin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• ATP-Binding Cassette Transporters (metabolism)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Humans
• Lignans
• Magnetic Resonance Spectroscopy
• Mass Spectrometry
• Molecular Conformation
• Multidrug Resistance-Associated Proteins
• Podophyllotoxin (analogs & derivatives, chemical synthesis, pharmacology)
• Structure-Activity Relationship
• Tetrahydronaphthalenes (chemical synthesis, chemistry, pharmacology)
• Tumor Cells, Cultured