Structural and stereochemical requirements of the spiroketal group of hippuristanol for antiproliferative activity

Abstract

Hippuristanol is a natural product that has recently been shown to inhibit eukaryotic translation initiation and tumor cell proliferation. To investigate the structure-and-activity relationship of hippuristanol, we synthesized a series of analogs by expanding the size of its F ring and determined their effects on the proliferation of cancer cell lines. All changes to the F ring of hippuristanol resulted in 3-fold to >100-fold decrease in activity.

The proteomics of quiescent and nonquiescent cell differentiation in yeast stationary-phase cultures

“…Abundant proteins were also involved in an NADPH-generating step of the pentose phosphate pathway (Gnd1p), which is required for resistance to oxidative stress (Izawa et al , 1998 ), and glucose kinase (Hxk2p), which is required for competitive fitness and growth on fermentable carbon sources (Kaeberlein et al , 2005 ). Finally, abundant proteins included the vacuolar ATPase (Tfp1p), required for resistance to a variety of stresses (Stevens and Forgac, 1997 ), and the translation initiation factor eIF4a (Tif2p), a DEAD/DEAH-box RNA helicase that is a current target for cancer therapeutics (Lindqvist and Pelletier, 2009 ; Li et al , 2010 ). This is consistent with the hypothesis that a major role for SP proteins is in stress resistance.…”

Hippuristanol - A potent steroid inhibitor of eukaryotic initiation factor 4A

“…The R stereochemistry at C22 is essential for activity 32 as are the gem-dimethyl substitutions on the F ring. 110 Appending functionalities onto R1 results in a 3-fold decrease in activity, whereas altering the R 2 OH leads to a 25-fold decrease in activity. 32,109 Converting the R 4 OH to a ketone or acetate diminishes activity approximately 25-and >2000 -fold, respectively.…”

Stereoselective Synthesis of Difructose Dianhydrides by Use of the Xylylene Group as Stereodirecting Element in Spiroketalisation Reactions

“…was added, and the solution was further stirred for 1 h. Et 2 O (10 mL) and water (10 mL) were added, and the organic layer was decanted, dried and concentrated. , 1 H, 4α-H), 3.93 (d, 1 H, 3β-H), 3.92 (d, J 1a,1b = 12.4 Hz, 1 H, 1a-H [21] (275 mg, 0.51 mmol) in dry DMF (3.1 mL), and the suspension was stirred under Ar at room temperature for 1 h. A solution of 1,2-bis(bromomethylbenzene) (603 mg, 2.54 mmol, 5 equiv.) in dry DMF (3.1 mL) was then added, the reaction mixture was further stirred under Ar for 3 h and quenched by addition of water (0.63 mL), and the solvents were evaporated.…”

“…[21] To investigate the effects of simultaneous conformational and distance constraints on the stereochemical outcome of the reaction, the o-, m-and p-xylylene-bridged precursors 36-38 (Scheme 6) were synthesised. Use of the two first linkers led preferentially to products of intramolecular glycosylation/spirocyclisation.…”

“…[16][17][18][19] Many of these compounds exhibit important biological activities, and consequently there is sustained interest in the controlled construction of this structural motif. [20][21][22][23][24][25][26][27][28][29] Up to six different tricyclic cores and 14 DFA isomers (types I-VI, Figure 1) differing in the ring sizes, linking positions and stereochemistry of the spiroketal centres have been identified in caramel or in chemically obtained mixtures. [7] This structural and stereochemical diversity makes DFAs ideal targets for evaluating new synthetic methodologies.…”