Flexible and enantioselective access to jaspine B and biologically active chain-modified analogues thereof

Abstract

Whereas the all-cis tetrahydrofuran framework of the cytotoxic anhydrophytosphingosine jaspine B is considered as a relevant pharmacophore, little is known about the influence of the aliphatic chain of this amphiphilic molecule on its activity. We developed a synthetic strategy allowing flexible introduction of various lipophilic fragments in the jaspine's skeleton. The route was validated with two distinct approaches to jaspine B. Five chain-modified analogues were also prepared. Biological evaluation of these derivatives demonstrated a good correlation between their cytotoxicity and their capacity to inhibit conversion of ceramide into sphingomyelin in melanoma cells. A series of potent and selective inhibitors of sphingomyelin production was thus identified. Furthermore, the good overall potency of an omega-aminated analogue allowed us to dissociate of the pharmacological action of jaspine B from its amphiphilic nature.

Practical Synthesis of Pachastrissamine (Jaspine B), 2-<i>epi</i>-Pachastrissamine, and the 2-<i>epi</i>-Pyrrolidine Analogue

“…Late-stage introduction of the side-chain makes it easy to synthesize derivatives bearing various side chains at the C-2 position. 7,16,27) To construct the cyclic structure of 5, we planned to employ cyclization of monotosylate 7. Compound 7 would be obtained from 1,2,4-triol 9 via selective tosylation of the primary alcohols catalyzed by dibutyltin oxide (Bu 2 SnO).…”

“…6) Andrieu-Abadie and colleagues also reported that 1 induces apoptosis in murine B16 melanoma cells through an increase in intracellular ceramide levels resulting from inhibition of the activity of sphingomyelin synthase. 7,8) Moreover, 1 was demonstrated to inhibit several kinases such as sphingosine kinase (SphK), cyclin-dependent kinase 2, and extracellular regulatory kinase. 9,10) Because of its novel structural features and impressive biological activity, many total syntheses of 1 have been accomplished.…”

“…It is a naturally occurring, novel anhydrophytosphingosine derivative that contains an all-cis-2,3,4-trisubstituted tetrahydrofuran ring with the (2S,3S,4S) absolute configuration and exhibits cytotoxic activity against various human cancer cell lines. [1][2][3][4][5][6][7][8][9] Recently, Delgado and colleagues reported that 1 causes autophagy mediated by dihydroceramides in human A549 lung cancer cells. 6) Andrieu-Abadie and colleagues also reported that 1 induces apoptosis in murine B16 melanoma cells through an increase in intracellular ceramide levels resulting from inhibition of the activity of sphingomyelin synthase.…”

“…9,10) Because of its novel structural features and impressive biological activity, many total syntheses of 1 have been accomplished. [3][4][5][6][7][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] The stereoisomers of 1 have also been synthesized, 5,6,[20][21][22][23][24][25][26][27][28][29][31][32][33][34][35][36][37][38][39][40] and their biological activity investigated. Interestingly, the 2-epimer 2 6,…”

“…10) Several pachastrissamine analogues have also been synthesized. 7,[41][42][43][44][45][46] Among them, the pyrrolidine analogue 3 was found to have better pharmacological properties than 1. 43) This difference in activity may be because of the fact that 3 can exist in multiple ionized forms.…”