Inhibition of Cyclin-Dependent Kinase Activity and Induction of Apoptosis by Preussin in Human Tumor Cells

Abstract

In this paper, we report that (؉)-preussin, a pyrrolidinol alkaloid originally identified as an antifungal agent, has growth-inhibitory and cytotoxic effects on human cancer cells. Preussin was found to be a potent inhibitor of cyclin E kinase (CDK2-cyclin E) in vitro (50% inhibitory concentration; ϳ500 nM) and to inhibit cell cycle progression into S phase. In agreement with these findings, the level of the cyclin-dependent kinase inhibitor p27 KIP-1 is increased in response to preussin treatment while the expression of both cyclin A and the transcription factor E2F-1 is down-regulated. Preussin also induces programmed cell death (apoptosis), which requires caspase activation and involves the release of cytochrome c from mitochondria. This induction of apoptosis is not blocked by high levels of Bcl-2, which usually confers resistance to chemotherapeutic agents. Taken together, our data indicate that preussin could be a promising lead compound for the development of a new class of potent antitumor drugs.

A Concise Total Synthesis of Antifungal Antibiotic (+)‐Preussin

“…of (S)-BINOL, 1 equiv. of Ti(O-iPr) 4 and 4-Å molecular sieves, which had been premixed at reflux temperature in CH 2 Cl 2 , the reaction of n-decanal and allyltributylstannane provided the homoallylic alcohol 4 [9a] in 82 % yield and 94 % ee [10] { Acetylation of the hydroxy function with acetic anhydride catalyzed by iodine [11] followed by oxidative cleavage of the olefinic bond using OsO 4 and NaIO 4 in the presence of 2,6-lutidine in dioxane/water [12] furnished the corresponding aldehyde 3. This aldehyde without further purification was subjected to Shibasaki's asymmetric nitro-aldol reaction [13] with 2-phenyl-1-nitroethane in the presence of the La-(R)-BINOL complex in THF at -50°C to deliver the nitro alcohol 6 in 73 % yield with a satisfactory diastereoselectivity (diastereomeric ratio = 20:1, as determined by 1 H NMR spectroscopy).…”

“…A mixture of (S)-BINOL (0.24 g, 0.84 mmol) and Ti(O-iPr) 4 (0.24 g, 0.84 mmol) in CH 2 Cl 2 (15 mL) in presence of 4-Å molecular sieves (2.4 g) was stirred under reflux. After 1 h the reaction mixture was cooled to room temperature, ndecanal (1.3 g, 8.3 mmol) was added and the resulting mixture was stirred for 10 min.…”

“…The organic phase was dried (Na 2 SO 4 ), the solvent evaporated and the residue purified by chromatography on SiO 2 (EtOAc/PE, 1:10) 1, 24.2, 25.0, 28.8, 29.5, 29.7, 33.1, 37.6, 54.2, 58.2, 71.1, 82.0, 126.9, 128.1, 137.9, 153.6 (2S,3S,5R)-2-Benzyl-3-hydroxy-1-methyl-5-nonylpyrrolidine (1): LiAlH 4 (0.36 g, 9.3 mmol) was added to a solution of N-Boc-pyrrolidine 9 (0.45 g, 0.93 mmol) in THF (10 mL) and the mixture was refluxed. Upon completion the mixture was cooled to 0°C and a saturated NH 4 Cl solution (15 mL) was added slowly followed by water (30 mL). The resulting solution was then extracted with diethyl ether (3 × 50 mL), the combined extracts were washed with brine and dried (Na 2 SO 4 23.0, 25.6, 28.9, 29.4, 29.7, 30.2, 32.0, 33.1, 34.6, 40.2, 47.8, 66.1, 71.1, 72.8, 126.9, 128.1, 132.9, 138.9 H 11.11, N 4.41; found C 79.52, H 11.17, N 4.37. …”

“…[3] Detailed biological studies by Muller and co-workers revealed that (+)-preussin induces apoptosis in human tumor cells. [4] It was also found in vitro to be a potent inhibitor of cyclin E kinase (CDK2-cyclin E) with a 50 % inhibitory concentration of around 500 n.…”

A Short Synthesis of Preussin: Use of Allyldimethylsilyl as Masked Hydroxyl

“…and Aspergillus ochraceus 2a and having strong inhibitory activity as broad-spectrum antibiotics against filamentous fungi, 2b the pyrrolidine alkaloid Preussin has been the target of many synthetic endeavors due to its tri-cis-pyrrolidine structure. 3 Recent observations of the role of Preussin in inhibition of the fission yeast ts mutants defective on cdc2-regulatory genes, 4 apoptosis-induction, inhibition of cyclin-E kinase, 5 and inhibition of programmed-1 ribosomal frameshifting, 6 have rekindled interest in synthesis of Preussin and its analogs. Suitably substituted silyl group can be treated as synthetically equivalent to hydroxyl function 7 and a synthetic approach using dimethylphenylsilyl group in place of ring hydroxy function has been reported.…”