Synthesis of Chondramide A Analogues with Modified β‐Tyrosine and Their Biological Evaluation

Abstract

Starting from cinnamates 9, obtained by Wittig reaction or Heck coupling, the diols 17 were prepared by asymmetric dihydroxylation. This was followed by a regioselective substitution of the 3-OH group with hydrazoic acid under Mitsunobu conditions. Methylation of the 2-OH group and reduction of the azide group led to the β-tyrosine derivatives 8. Condensation with the dipeptide acid 6 furnished the tripeptide part of the chondramides. The derived acids 21 were combined with the hydroxy ester 7 to the esters 22. Cleavage of the tert-butyl groups and intramolecular lactam formation gave rise to the chondramide A analogues 2b–k. Growth inhibition assays showed most of the analogues to be biologically active. Some of them even reach the activity of jasplakinolide. It can be concluded that the 4-position of the aryl ring in the β-tyrosine of chondramide A tolerates structural modifications quite well.

Synthetic Chondramide A Analogues Stabilize Filamentous Actin and Block Invasion by Toxoplasma gondii

“…This same series of compounds has previously been used to examine growth inhibition of human cells, and they are also highly potent, with EC 50 values ranging from 0.03 to 0.30 μM, with the exception of 2k , which is much less potent (i.e., EC 50 ∼1.4 μM). 47 …”

“…43 The complete chemical synthesis and compound derivatization have been investigated based on 2 and 4 scaffolds, allowing generation of a number of structurally related analogues. 44−47 Taking advantage of these developments, we previously reported schemes for efficient chemical synthesis of 2 as a means of generating increased diversity of chondramides, and these compounds were shown to disrupt actin and inhibit mammalian cell division. 45,47 In the present study, we compared the activities of natural compounds 2 – 4 as well as 10 previously described synthetic analogues ( 2b – k ) for their ability to stabilize F-actin in vitro and block infection of T. gondii in vitro .…”

“…44−47 Taking advantage of these developments, we previously reported schemes for efficient chemical synthesis of 2 as a means of generating increased diversity of chondramides, and these compounds were shown to disrupt actin and inhibit mammalian cell division. 45,47 In the present study, we compared the activities of natural compounds 2 – 4 as well as 10 previously described synthetic analogues ( 2b – k ) for their ability to stabilize F-actin in vitro and block infection of T. gondii in vitro . Although the compounds tested here do not show selectivity for parasite over host actin, they nonetheless are potent inhibitors of parasite invasion and provide useful leads for future development of more specific compounds.…”

A Diels–Alder Approach to a Communesin Model: A/B‐Cyclization Route

“…Compound 15: HN 3 (freshly prepared 2.0 M solution;18 1.4 mL, 2.89 mmol, 5.0 equiv.) was added dropwise to a suspension of 5 (300.9 mg, 0.578 mmol) and Ph 3 P (651.6 mg, 2.31 mmol, 4.0 equiv.)…”

Synthesis of Simplified Halogenated Chondramide Derivatives with Strong Cytostatic Properties

“…The N ‐terminal alanine can be replaced by a protected lysine, what also allows the incorporation of fluorescence labels at this position 15. Maier et al could show that in the C ‐terminal β‐tyrosine the OH group can be replaced by several other substituents without dramatically changing the activity 8d…”