Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring

Abstract

Migrastatin and isomigrastatin analogues have been synthesised in order to contribute to structure–activity studies on tumour cell migration inhibitors. These include macrocycles varying in ring size, functionality and alkene stereochemistry, as well as glucuronides. The synthesis work included application of the Saegusa–Ito reaction for regio‐ and stereoselective unsaturated macroketone formation, diastereoselective Brown allylation to generate 9‐methylmigrastatin analogues and chelation‐induced anomerisation to vary glucuronide configuration. Compounds were tested in vitro against both breast and pancreatic cancer cell lines and inhibition of tumour cell migration was observed in both wound‐healing (scratch) and Boyden chamber assays. One unsaturated macroketone showed low affinity for a range of secondary drug targets, indicating it is at low risk of displaying adverse side effects.

Synthesis and Biological Evaluation of Migrastatin Macrotriazoles

“…Purification by distillation (0.05 mbar, T = 60 °C, 12 h) allowed the removal of pinenol derived from the (+)‐Ipc 2 BOMe. The distillation under reduced pressure allowed us to improve the yield previously reported by Murphy; we were able to avoid the removal of the benzoyl ester, double protection with the TBS ( tert ‐butyldimethylsilyl) group and selective cleavage to give the primary alcohol. The two diastereoisomers 11a and 11b were then submitted to protection of the secondary alcohol and hydrolysis of the benzoate to give compounds 13 .…”

“…Alkenylazide synthon 9 was prepared by activation of 5‐hexen‐1‐ol ( 8 ) with methanesulfonyl chloride and subsequent treatment with sodium azide. The preparation of the advanced intermediates 12a and 12b was accomplished[5b] by Brown's asymmetric allylation of aldehyde 10 , as described previously . The formation of the two new stereocentres implies that the treatment of allyl methyl ether in the presence of s ‐butyllithium results in the formation of a ( Z )‐allylic anion, which then reacts with (+)‐Ipc 2 BOMe (Ipc = isopinocamphenyl) to form an overall stabilized complex.…”

“…Ethyl (4 S ,5 S ,6 S , Z )‐5‐[( tert ‐Butyldimethylsilyl)oxy]‐6‐methoxy‐2,4‐dimethyl‐octa‐2,7‐dienoate (15b): Phosphonate B [5b] (218 mg, 0.65 mmol) in THF (11 mL) was treated with NaH (60 % in mineral oil; 31.2 mg, 0.78 mmol) at 0 °C, and the mixture was stirred for 1 h. The mixture was then cooled to –78 °C, and a solution of 14b (178 mg, 0.65 mmol) in THF (5 mL) was added. The mixture was stirred at –78 °C for a further 30 min.…”

“…In recent years, analogues characterized by the removal of the side chain (macroketone 2 ; Figure ) and the replacement of the ester group with an amide functionality (macrolactam 3 ) have been described. Our interest in the synthesis and modification of anticancer agents, and in particular our interest in migrastatin analogues, prompted us to consider the preparation of triazole‐containing migrastatin derivatives. We recently investigated the biological effects of replacing the amide group of different anticancer drugs with a 1,4‐disubstituted triazole ring …”

The Therapeutic Potential of Migrastatin-Core Analogs for the Treatment of Metastatic Cancer

“…In 2015 [ 18 ], Murphy and co-workers reported the preparation of several migrastatin-core analogs with variations in the macrocycle ring size and functionality. Therefore, advanced intermediate 8 was used for the preparation of compounds MGSTA-8 to MGSTA-16 .…”