Pilar Gallego

Synthesis of a series of 3-cyanopropionamides and 4-imino-γ-butyrolactams and evaluation of their function as modulators of multidrug resistance

The synthesis of the 3‐cyanopropionamides 3a and 3b, of the 2,2‐dimethyl‐3‐cyanopropionamides 4a—4c and of the 4‐imino‐γ‐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, accesible 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‐μM concentration.

Free Radical Cyclization of Acyclic Sugar Dithioacetals: An Approach to Mannostatin A Analogues

Abstract The tributyltin hydride + AIBN mediated free radical cyclization of oxime ethers tethered dithioacetals 6 and 12, obtained from D-ribose or D-glucose, respectively, is reported. The desired carbocycles 7, 8 and 14 have been obtained in good yield and moderate diastereoselectivity. These products are new mannostatin A analogues.

Use of lactamide diastereoisomers to permit resolution of a racemic modulator of cancer drug resistance

The synthesis of enantiomers of an amidic modulator of cancer multidrug resistance, the chirality of which is not prone to chromatography, has been carried out via formation of the diastereoisomeric esters of the precursor racemic acid with (S)-lactamide and separation of the esters on silica gel.