Treatment of the thioethers (RNH-o-C 6 H 4 ) 2 S (H 2 [R 2 NSN]; R ) Xy, Xyf; Xy ) 3,5-Me 2 C 6 H 3 , Xyf ) 3,5-(CF 3 ) 2 C 6 H 3 ) with 2 equiv of n-BuLi followed by addition of 0.5 equiv of [(η 6 -C 6 H 6 )-RuCl 2 ] 2 in THF gave the bis(diarylamido)/thioether complexes [(η 6 -C 6 H 6 )Ru[R 2 NSN]] (R ) Xy (1a), R ) Xyf (1b)) in moderate yields. In the presence of 1a (1 mol %) and PCy 3 (2 mol %; Cy ) cyclohexyl), benzonitrile was catalytically hydrogenated to give benzylamine (72%) and benzylidenebenzylamine (27%) at 80 °C and 30 atm, while the hydrogenation with 1b as a catalyst precursor resulted in the formation of benzylamine (37%) and benzylidenebenzylamine (51%) under the same reaction conditions. The yield of benzylamine was improved up to 92% by using a catalyst mixture of 1a (1 mol %)/PCy 3 (2 mol %)/t-BuONa (10 mol %). On the other hand, the reaction of 1a with excess PMe 3 afforded the tris(trimethylphosphine) derivative [(PMe 3 ) 3 Ru[Xy 2 NSN]] (2). Treatment of 2 with excess PhCN, MeCN, or N 2 H 4 ‚ H 2 O resulted in the replacement of a PMe 3 ligand by these substrates to give [(PMe 3 ) 2 LRu-[Xy 2 NSN]] (3, L ) PhCN; 4, L ) MeCN; 5, L ) N 2 H 4 ), while the reaction of 2 with benzoylhydrazine gave the κ 2 -benzoylhydrazido complex [(PMe 3 ) 2 Ru(κ 2 -(O,N)-PhC(O)d NNH 2 )(H[Xy 2 NSN])] (6). Structures of 1a, 1b, 2, 5, and 6 have been determined by X-ray crystallography.

HeLa/CDDP cells showed decreased activity and expression of MDR1 and overexpression of gamma-GT but not gamma-GCS whereas the activity of MDR1 in HeLa/TXL cells was significantly enhanced. Thus, the molecular changes to HeLa cells caused by continuous exposure to cisplatin or paclitaxel were in part clarified, and therefore an understanding of the cellular changes induced by chemotherapeutic agents will be necessary to establish a strategy for reversing MDR.

No abstract

The popularity of traditional herbal medicine (THM) being used as complementary medicines or alternative medicines is increasing. On the other hand, the development of multidrug resistance (MDR) remains a major hurdle to successful cancer chemotherapy. Some THMs capable of reversing MDR may contribute to the improvement of clinical outcomes in cancer chemotherapy. Herein, 19 kinds of herb were chosen from the ingredients of major THMs, and their effects on the sensitivity to anticancer drugs of tumor cells were investigated using the human cervical carcinoma HeLa cells. Focusing on the major mechanism for MDR, i.e., MDR1/P-glycoprotein, the effects of herbal extracts on its transport function were also examined using a MDR1 substrate Rhodamine123. Glycyrrhizae Radix, Rhei Rhizoma, Scutellariae Radix, Poria, Zizyphi Fructus, Zingiberis Rhizoma (dry), Coptidis Rhizoma, Ephedrae Herba and Asiasari Radix significantly enhanced the sensitivity to a MDR1 substrate paclitaxel, whereas none of the herbal extracts used had any effect on the sensitivity to 5-fluorouracil, which is not a substrate for MDR1. Rhodamine123 uptake was significantly increased by Rhei Rhizoma, Poria or Ephedrae Herba among nine herbal extracts sensitized to paclitaxel. This suggests that the increase in paclitaxel sensitivity by Glycyrrhizae Radix, Rhei Rhizoma, Poria or Ephedrae Herba was caused, in part, by the inhibition of MDR1 function, and the change in paclitaxel sensitivity by the other herbal extracts was not always dependent on this. Collectively, these findings indicate that the combination of anticancer drugs with some herbal extracts contributes to the enhancement of clinical outcomes in cancer chemotherapy.

Pretreatment for 3 days with oral ofloxacin or norfloxacin had no significant effect on the disposition of a single i.v. dose the theophylline in healthy volunteers.