Synthesis and cytotoxic evaluation of new (4,5,6,7-tetrahydro-indol-1-yl)-3-R-propionic acids and propionic acid ethyl esters generated by molecular mimicry.

Abstract

Indolones 4 and 5, and indolyl-aminoacids 6a-e, 7a-e, and 8a and 8b were designed by structural modification of lead compound 3. These compounds were tested on six tumor cell lines to determine the role of the azepinone ring and the N-phenyl substituent in the cytotoxicity of 3. Our results show that 4 and 5 have dramatically reduced cytotoxicity, due to the loss of the azepinone moiety of lead compound 3. In contrast, indolyl-aminoacids 6a, 7a, and 8a (N-(L)-cysteine ethyl ester derivatives) inhibited the proliferation of almost all cancer cell lines tested, even though they lack the azepinone ring. In addition, derivative 6c (N-(D)-alanine methyl ester group) was selectively cytotoxic to HCT-15 cells. Preliminary structure-activity relationship (SAR) studies with these compounds revealed the importance of the ethyl ester moiety on the amino acid moiety. Compounds 6a-e, 7a-e, and 8a and 8b were obtained in good yields by a catalytic Paal-Knorr reaction carried out under microwave irradiation using commercially available chiral amino esters or amino acids and 1,4-dicarbonyl compounds.

• Authors: Roberto Martínez, Angel Clara-Sosa, Ma Teresa Ramírez Apan
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 15 Issue 11 Pg. 3912-8 (Jun 01 2007) ISSN: 0968-0896 [Print] England
• PMID: 17395468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Esters
• Indoles
• Propionates

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Esters (chemical synthesis, chemistry, pharmacology)
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Molecular Mimicry
• Propionates (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship