title: Synthesis of a series of 3-cyanopropionamides and 4-imino-gamma-butyrolactams and evaluation of their function as modulators of multidrug resistance.
abstract: The synthesis of the 3-cyanopropionamides 3a and 3b, of the 2,2-dimethyl-3-cyanopropionamides 4a-4c and of the 4-imino-gamma-butyrolactams 5a and 5b (cyclic functional isomers of 3-cyanopropionamides) is described. The amides 3a and 3b were obtained by aminolysis of the corresponding acid chlorides, which are accessible via hydrolysis of the ethyl esters to the acids. This methodology was not used for the synthesis of the amides 4a-4c owing to steric hindrance to hydrolysis in the corresponding ethyl esters. These nonreactive esters, accessible by alkylation of 1-cyano carbanions with ethyl bromodimethylacetate, could be directly converted into the amides 4a-4c by aminolysis with the lithium amide of 3,4-dimethoxy-N-methylphenethylamine. Instead of open-chain amides, the lactams 5a and 5b are obtained when the lithium amide of 3,4-dimethoxyphenethylamine (i.e., of a primary rather than secondary amine) is used for the aminolysis. The synthesized compounds were tested for their ability to decrease the resistance to vincristine in a multidrug-resistant subline of murine leukemic lymphoblasts that are 300-fold resistant to the antiproliferative drug. The amides 4a and 4c, and lactam 5a, all of which have a highly branched carbon backbone, were active. Lactam 5a reduced the vincristine resistance by 90% at a 2-microM concentration.
authors.affiliation: Instituto de Química Médica, CSIC, Madrid, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Ros
authors.forename: R
authors.initials: R
authors.lastname: García
authors.forename: P
authors.initials: P
authors.lastname: Gallego
authors.forename: A
authors.initials: A
authors.lastname: Sánchez-Caballero
authors.forename: M P
authors.initials: MP
authors.lastname: Rivera-Fillat
authors.forename: M R
authors.initials: MR
authors.lastname: Grau-Oliete
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D018432:Drug Resistance, Multiple; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000577:Amides; D007769:Lactams; D014750:Vincristine; C034666:propionamide