Synthesis and migrastatic activity of cytochalasin analogues lacking a macrocyclic moiety

Abstract

Macrocyclic moiety is not essential for the biological activity of cytochalasan analogues.

Synthesis of cytochalasan analogues with aryl substituents at position 10

“…Compounds 23 , 25 , 27 , and 28 showed moderate activity similar to or lower than the cytotoxic effect of previously reported derivative 21 . 21 On the other hand, after 72 h treatment, methyl derivative 22 , phenoxyphenyl 24 and phenanthrenyl 26 derivatives did not show sufficient activity (IC 50 > 50 μM), indicating that the presence of an aryl moiety improves the cytotoxic effect, however, the bulkiness, and/or sterical factors need to be considered to maintain the activity.…”

“…This structural analogue was chosen based on our previous work showing that cytochalasan analogues lacking the macrocyclic moiety still exhibit biological activities. 21 The key step of the synthesis is the formation of the perhydroisoindolone core by the Diels–Alder reaction. First, we considered N -MOM protection of a dienophile but the approach failed due to dienophile instability (data not shown).…”

“…The aliphatic side chain was introduced using our previously published procedure (Scheme 4). 21 The hydroxy group of compound 16 was alkylated with a triflate that was generated in situ from (2-iodoethyl)benzene using silver triflate and 2,6-di- tert -butylpyridine. Derivative 17 was synthesized with a high yield of 90%.…”

“…This compound was synthesized in analogy with a known procedure. 21 To a solution of compound 12 (100 mg, 0.26 mmol) in anhydrous THF (1 mL), LiHMDS (0.38 mL, 1.0 M in THF, 0.38 mmol) was added at −78 °C under argon. After 1 h, a solution of PhSeCl (74 mg, 0.38 mmol) in dry THF (1 mL) was added dropwise and the reaction mixture was stirred at −78 °C until full conversion (3 h, TLC, hexanes/EtOAc: 4/1).…”

“…This compound was synthesized in analogy with a known procedure. 21 AgOTf (2.4 g, 9.3 mmol) was dried under a high vacuum (heat gun 150–200 °C). Then, a solution of compound 16 (1.6 g, 3.1 mmol) in dry DCM (3 mL) followed by 2,6-di- tert -butylpyridine (2.4 mL, 10.9 mmol) and dry DCM (20 mL) were added at 0 °C under argon atmosphere.…”