Amino acids as chiral building blocks. Synthesis of anti-beta-amino alcohols and dipeptides with antiproliferative activity.

  1. Rodolfo Gastón Silveira Dorta
Supervised by:
  1. José Manuel Padrón Carrillo Director

Defence university: Universidad de La Laguna

Year of defence: 2015

  1. Química Orgánica

Type: Thesis


In this work, we show that enantiomerically pure anti-betas-amino alcohols were synthesized from optically pure beta-N,N-dibenzylamino benzyl esters, derived from alpha-amino acids. The synthesis was carried out by the sequential reduction to aldehyde at -78 ºC with DIBAL-H and subsequent in situ addition of Grignard reagents. With this methodology in hand we were able to obtain anti-beta-amino alcohols, anti-2-amino-1,3-diols and anti-3-amino-1,4-diols in good yields (60-95%) and excellent stereoselectivity (de > 95%). This technique was also compatible with free hydroxyl groups present in the substrate. To demonstrate the versatility of the method, a small and structure-biased library of enantiopure anti-beta-amino alcohols (sphinganine and spisulosine analogues) was prepared in a straightforward manner. Their antiproliferative activity was tested against a panel of five human solid tumor cell lines gave GI50 values in the range 1-20 µM. The reverse screening by computational methods against 58 proteins involved in cancer pointed out kinases as possible therapeutic target candidates. The experimental determination of the interaction with 456 kinases indicated that the compounds behave as selective CK1epsilon inhibitors. These findings have demonstrated that the lead compound represents the first selective CK1epsilon inhibitor with proven antiproliferative activity in cancer cell lines. Furthermore, in the present work we explored the regioselective benzylation of L-glutamic acid under substoichiometric amounts of the alkylating agent. Our results demonstrated unambiguously that N,N-dibenzylglutamic acid alpha-benzyl ester was not obtained by direct benzylation of L-glutamic acid as reported by other authors. Instead, under such reaction conditions N,N-dibenzylglutamic acid gamma-benzyl ester was obtained. Then, a small and focused library of 22 dipeptides derived from N,N-dibenzylglutamic acid alpha- and gamma-benzyl esters was prepared in a straightforward manner. Their antiproliferative evaluation in the human solid tumor cell lines provided gamma-glutamyl methionine (GI50 = 6.0-41 microM) and alpha-glutamyl proline (GI50 = 7.5-18 microM) as lead compounds. In particular, glutamyl serine and glutamyl proline dipeptides were more active in the resistant cancer cell line WiDr than the conventional anticancer drugs cisplatin and etoposide. Glutamyl tryptophan dipeptides did not affect cell growth of HBL-100, whilst in T-47D cells proliferation was inhibited.