Myristoleic acid, a cytotoxic component in the extract from Serenoa repens, induces apoptosis and necrosis in human prostatic LNCaP cells.

BACKGROUND: Prostatic tumors are well known to progress to hormonal therapy-resistant terminal states. At this stage, there are no chemotherapeutic agents to affect clinical outcome. An effective cell death inducer for these prostate cells may be a candidate as an attractive antitumor agent. The extracts from S. repens have been used to improve the state of prostatic diseases and we have attempted to identify the effective component from the extract. METHODS: Cell viability was examined in LNCaP cells, an in vitro model for hormonal therapy-resistant prostatic tumor. RESULTS: We found that exposure of the extract from S. repens resulted in cell death of LNCaP cells. We also identified myristoleic acid as one of the cytotoxic components in the extract. The cell death exhibited both apoptotic and necrotic nuclear morphology as determined by Hoechst 33342 staining. Cell death was also partially associated with caspase activation. CONCLUSIONS: It was demonstrated that the extract from S. repens and myristoleic acid induces mixed cell death of apoptosis and necrosis in LNCaP cells. These results suggest that the extract and myristoleic acid may develop attractive new tools for the treatment of prostate cancer.

Highly chemoselective hydrogenation with retention of the epoxide function using a heterogeneous Pd/C-ethylenediamine catalyst and THF

In general, palladium-carbon (Pd/C) catalyzed hydrogenation of epoxides affords the corresponding primary and secondary alcohols as a mixture. It has been found that the catalytic activity of a Pd/C -ethylenediamine complex catalyst [Pd/C(en)] in the hydrogenolysis of epoxide functions is drastically reduced. Herein we describe a mild and chemoselective method for the hydrogenation of olefin, nitro, and azide functions with retention of the epoxide function. The chemoselectivity was accomplished by using a combination of 5% Pd/C(en) and THF as solvent. A significant drop in the chemoselectivity of the hydrogenation is observed with 5% Pd/C(en) in MeOH. These results reinforce the utility of epoxides as important precursors of alcohols in synthetic chemistry.

[Development of a novel type of Pd/C-catalyzed chemoselective hydrogenation using a nitrogen catalyst poison].

The development of modified Pd catalysts for chemoselective hydrogenation has been a long-standing goal in synthetic chemistry. Several applications of catalyst poisons for this purpose have been studied. But these methods usually lack rules of generality except for a few examples such as Lindlar catalyst and Rosenmund's reaction. Recently, we found that the addition of a nitrogen containing base such as ammonia, triethylamine, pyridine, ammonium acetate, to a Pd/C-catalyzed reduction system selectively inhibited the hydrogenolysis of an aliphatic benzyl ether with smooth hydrogenation of other reducible functions such as olefin, N-Cbz, benzyl ester and azido. However, the selective suppression of hydrogenolysis was not applicable to the benzyl protective group with phenolic hydroxyl functions. The problem has been temporarily, solved by the employment of a 4-methoxybenzyl (MPM) protective group instead of the more reducible benzyl group with phenolic hydroxyl functions. During the course of our further study on the Pd/C-catalyzed chemoselective hydrogenolysis, we further found large differences in the suppressive effect on the hydrogenolysis of O-benzyl protective groups depending upon the nitrogen-containing bases employed as additives. By the use of Pd/C-2,2'-dipyridyl combination as a catalyst for the hydrogenation, aliphatic and phenolic O-benzyl protective groups can be retained without any hydrogenolysis. Further-more, we found that the Pd/C catalyst formed an isolable complex with ethylenediamine employed as a catalytic poison, selectively catalyzing the hydrogenation of various functional groups without hydrogenolysis of O-benzyl protective groups even in phenolic benzyl ethers.

Synthesis of 2,3-dihydroinosine derivatives by reduction using BH3-THF.

A novel reductive method for the chemical modification of nucleosides is described. Reaction of inosine derivatives with boran-THF resulted in the regioselective reduction of purine ring to afford the corresponding 2,3-dihydroinosine derivatives in moderate yields.

Facile method for the preparation of 7-methyl-8-oxoguanosines as an immunomodulator.

Reaction of 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-7-methylguaninium iodide (2a) with hydrogen peroxide in acetic acid gave the corresponding 7-methyl-8-oxoguanosine derivative (3a) in good yield. Deprotection of 3a easily gave 7-methyl-8-oxoguanosine (1), which is well-known as an immunomodulator. Substitution of acetyl group at the N2-position of guanine ring accelerated the oxidation reaction of the 7-methylguaninium iodide.

Synthesis of 6-aminouracils and pyrrolo[2,3-d]pyrimidine-2,4-diones and their inhibitory effect on thymidine phosphorylase.

Inhibitors of thymidine phosphorylase (dThdPase) are expected to suppress the growth and metastasis of tumor cells by inhibition of angiogenesis and were designed by utilizing the three dimensional structure of the enzyme. 5-Substituted 6-aminouracils (5) and 7-substituted pyrrolo[2,3-d]pyrimidine-2,4-diones (6) were synthesized and tested for inhibition of human placenta thymidine phosphorylase. 5-Bromo-6-aminouracil (5d), 5-cyano-6-[3-(methylamino)propyl]-uracil (5e), and 7-(2-aminoethyl)-pyrrolo[2,3-d]pyrimidine-2,4-dione (6c) inhibited dThdPase with IC50s of 7.6, 3.8 and 44.0 microM, respectively.

Novel reactions of 5-bromouracil derivatives with active methylene compounds.

5-Bromouracil derivatives (1) reacted with carbanions at room temperature to give 6-substituted uracils (6), 2,4-diazabicyclo[4,1,0] heptanes (8) and 2,4-diazabicyclo[4,3,0]nonane derivative (9), which depend largely upon the structure of the active methylene compounds employed for the generation of carbanions.