Synthetic Strategies Towards the Generation of Penicillin‐Containing Hybrids in the Search for Anticancer Activity

Abstract

An extended library of hybrids that combined a penicillinderivative with a peptoid moiety was designed and synthetized usingeither a solid-phase or a mixed solid-phase/solution-phase strategy.The library was further evaluated for antiproliferative activity. Whilenone of the different synthesized compounds showed significantcytotoxicity against a normal cell line, tumor cell results drew severalconclusions, when comparing with our reference, the highly activetriazolylpeptidyl penicillin derivative, TAF7f. Thus, when the 1,2,3-triazole group was exchanged by its “retro-inverse” analogue, nochange was noted no change was noted in the activity of the hybrids;however, better performance was generally obtained if the triazole isreplaced by a glycine moiety. Additionally, the absence of hydrogenbond donor groups decreased the compounds activity, which couldexplain that, in general, this set of derivatives were less active thantheir peptide-containing analogues. From this study, is indisputablethat, regardless of the type of chain (peptide, peptoid or mixture)attached to penicillin, an isobutyl side chain placed in the positionclosest to penicillin and a benzyl in the next position are determinantfor the activity.