A Strategy for the Generation of Triazolylpeptidyl Penicillin Analogs in the Search for New Antitumoral Compounds

MARTIREN, NADIA L; CORNIER, PATRICIA G; MATA, ERNESTO G

Jornada; ACS SUMMER SCHOOL ON GREEN CHEMISTRY & SUSTAINABLE ENERGY; 2019

Introduction:The ability of small molecules to interact with macromolecules and perturb their normal functionhas emerged as a powerful tool for dissecting biological processes and became the leading strategy for drug discovery.Employing molecular hybridization methodology and a solid-phase organic chemistry approach,our research group synthesized a library of compounds that conjugate a penicillin derivative to apeptide through a triazole group.These compounds were evaluated as antiproliferative agents in vitro, and some of them showed an outstanding activity and selectivity.Results:Based on the structures of the aforementioned triazolylpeptidyl-penicillins, analogs were designedmodifying the peptide portion of the molecular hybrid, in order to improve of the pharmacokineticproperties and increase our understanding of the structure-activity relationship. A well establishedmethodology in these cases is the use of peptidomimetic, small molecules with the capacity to mimic the biological functions of the peptides without the disadvantage of the low bioavailability.In this research we were focus on the N-substituted glycine oligomers, otherwise referred as α-peptoids, a readily accessible class of synthetic, non-natural peptide mimic of modular design into which a plethora of structural elements can be readily incorporated. In our work, we decided to takeadvantage of the solid-phase synthesis as a methodology to obtain the α-peptoids and the subsequent assembly of the molecular hybrid.Our first approach consist of synthesizing a series of compounds in which the peptoid and thepenicillin moiety were attached by a glycine. In the second approach we tested a click reactionbetween the supported alkyne and the penicillin azide to provide the hybrid analogues.Conclusion:By the development of a solid-phase synthetic protocol, a small library of 10 compounds with moderate to good yields was obtained.The study of the effect of synthesized compounds on the growth of two tumor cell lines (HeLa: human cervix carcinoma and B16: murine melanoma) and epithelial cells derived from normal murine mammary gland (NMuMG) is currently in progress.