Synthesis of Simplified Halogenated Chondramide Derivatives with Strong Cytostatic Properties

Abstract

Removing the methyl groups and the stereogenic centers from the ω‐hydroxy acid of the chondramides results in a significant drop in the cytotoxicity of these interesting depsipeptides. This effect can be almost compensated for by introduction of a second chlorine atom on the β‐tyrosine moiety of the natural products. These simplified chondramides are much easier accessible than natural chondramides.

Synthesis and Biological Evaluation of Dichlorinated Chondramide Derivatives

“…Also included for reference are data for chondramide C, chondramide C1, and dichlorodesmethyl chondramide C, a synthetic analogue in which all the substituents on the polyketide unit are removed. In previous studies, we found this derivative to have comparable activity to chondramide C (at least towards HCT‐116 cells) 12…”

“…With hydroxy esters 5 and 16a in hand, we next focussed on the synthesis of the chondramide derivatives (Scheme ). Esterification of the OH functionality with chlorinated β‐tyrosine derivative 17 12 using the Steglich protocol27 gave the desired esters (i.e., 18 ) in excellent yield. Cleavage of the N ‐Boc ( tert ‐butoxycarbonyl) group and coupling with chlorinated tryptophan dipeptide A gave access to tripeptide esters 19 .…”

“…During the coupling step, a partial epimerization of the tryptophan was observed 12. This was not a serious issue since the “wrong” diastereomer could be removed by chromatography of the cyclic peptide.…”

“…Very recently, we showed that dichlorination significantly increases the cytotoxicity of chondramide derivatives. Even when the methyl substituents in the polyketide fragment were removed completely, the biological activity could be retained by introduction of a second chlorine atom into the β‐tyrosine (R 1 = R 2 = Cl) 12…”

“…Obviously, this position is suitable for modifications. To the best of our knowledge, (doubly) halogenated derivatives have not been investigated so far, except for our simplified chondramides described recently 12. Because of our ongoing interest in the synthesis of peptidic natural products, especially those with anticancer activity,16 we decided to also investigate the influence of the substitution pattern on the cytotoxicity of dichlorinated chondramides, focussing on the new ethyl‐substituted derivatives.…”