SYNTHESIS OF N-METHYLSUBSTITUTED INDOLOLACTONES AS SELECTIVE ACTIVATORS OF RAS GUANYL NUCLEOTIDE-RELEASE PROTEINS (RASGRP)

CYNTHIA L., GARCÍA; VICTOR, E. MARQUEZ; MARÍA J., COMIN; LUCÍA, GANDOLFI DONADÍO

Phyladelphia

Congreso; 236th ACS National Meeting; 2012

SYNTHESIS OF N-METHYLSUBSTITUTED INDOLOLACTONES AS SELECTIVE ACTIVATORS OF RAS GUANYL NUCLEOTIDE-RELEASE PROTEINS (RASGRP)     Cynthia L. García1, Lucía, Gandolfi Donadío1, Victor E. Marquez2and María J. Comin1   1Centro Investigación y Desarrollo en Química,  Instituto Nacional de Tecnología Industrial (INTI), Buenos Aires, Argentina. 2 Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA     N-methyl substituted dicaylglycerol-indololactones are effectors of PKC isoforms and exhibit substantial selectivity between RasGRP3 and aPKC, been 1 the most selective compound for RasGRP. In an effort to explore the influence of structural variations of these analogues on the activation selectivity, we have synthesized isomers 2 and 3 where the indole moiety is connected to the lactone through positions 6 and 7 of its phenyl ring. Conveniently protected lactone 4 was prepared starting from commercial 1,3-dihydroxiacetone 5 in four steps. The synthesis and selectivity between RasGRP and aPKC activation will be described.