Sang-sup Jew

Protective effects of asiaticoside derivatives against beta-amyloid neurotoxicity.

Asiaticoside (AS) derivatives were tested for potential protective effects against Aβ‐induced cell death. Of the 28 AS derivatives tested, asiatic acid (AA), asiaticoside 6 (AS6), and SM2 showed strong inhibition of Aβ‐induced death of B103 cells at 1 μM. The three AS derivatives were further tested for their effects on free radical injury and apoptosis. All three AS derivatives reduced H2O2‐induced cell death and lowered intracellular free radical concentration, but AA showed the strongest protection. In contrast, SM2 was the most effective blocker of staurosporine‐induced apoptosis. These results suggest that the three AS derivatives block Aβ toxicity by acting through different cellular mechanisms. When applied to hippocampal slices, AA, SM2, and AS6 did not alter n‐methyl‐D‐aspartic acid (NMDA) or non‐NMDA receptor‐mediated synaptic transmission, paired‐pulse facilitation or induction of long‐term potentiation in the field CA1. These results indicate that the three AS derivatives do not alter physiological properties of the hippocampus at the concentration that blocks Aβ‐induced cell death. Therefore AS6, AA, and SM2 can be regarded as reasonable candidates for a therapeutic Alzheimers disease drug that protects neurons from Aβ toxicity. J. Neurosci. Res. 58:417–425, 1999.

Trimeric Cinchona alkaloid phase-transfer catalyst: α,α′,α′′-tris[O(9)-allylcinchonidinium]mesitylene tribromide

A trimeric Cinchona alkaloid ammonium salt, α,α′,α′′-tris[O(9)-allylcinchonidinium]mesitylene tribromide has been prepared as a novel phase-transfer catalyst. The catalytic enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester using the trimer catalyst showed high enantioselectivity (90–97% ee).

Structure–activity relationship study of asiatic acid derivatives against beta amyloid (Aβ)-induced neurotoxicity

8 Semi-synthetic derivatives of asiatic acid were prepared and their protective effect against Aβ-induced neurotoxicity was evaluated. Among them, asiatic acid (2), and 4, 16 showed 97, 92 and 87% of protective effect, respectively.

Antitumor activity of 7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin, CKD602, as a potent DNA topoisomerase I inhibitor

We developed a novel water-soluble camptothecin analogue, CKD602, and evaluated the inhibition of topoisomerase I and the antitumor activities against mammalian tumor cells and human tumor xenografts. CKD602 was a nanomolar inhibitor of the topoisomerase I enzyme in the cleavable complex assay. CKD602 was found to be 3 times and slightly more potent than topotecan and camptothecin as inhibitors of topoisomerase, respectively. In tumor cell cytotoxicity, CKD602 was more potent than topotecan in 14 out of 26 human cancer cell lines tested, while it was comparable to camptothecin. CKD602 was tested for thein vivo antitumor activity against the human tumor xenograft models. CKD602 was able to induce regression of established HT-29, WIDR and CX-1 colon tumors, LX-1 lung tumor, MX-1 breast tumor and SKOV-3 ovarian tumor as much as 80, 94, 76, 67, 87% and 88%, respectively, with comparable body weight changes to those of topotecan. Also the therapeutic margin (R/Emax: maximum tolerance dose/ED58) of CKD602 was significantly higher than that of topotecan by 4 times. Efficacy was determined at the maximal tolerated dose levels using schedule dependent i.p. administration in mice bearing L1210 leukemia. On a Q4d×4 (every 4 day for 4 doses) schedule, the maximum tolerated dose (MTD) was 25 mg/kg per administration, which caused great weight loss and lethality in <5% tumor bearing mouse. This schedule brought significant increase in life span (ILS), 212%, with 33% of long-term survivals. The ex vivo antitumor activity of CKD602 was compared with that of topotecan and the mean antitumor index (ATI) values recorded for CKD602 were significantly higher than that noted for topotecan. From these results, CKD602 warrants further clinical investigations as a potent inhibitor of topoisomerase I.

Enantioselective synthesis of 20(S)-camptothecin using sharpless catalytic asymmetric dihydroxylation

The homochiral key intermediate 2 of 20(S)-camptothecin was prepared enantioselectively by using catalytic asymmetric dihydroxylation as the key reaction.

Highly efficient ortho-fluoro-dimeric cinchona-derived phase-transfer catalysts

A series of cinchona alkaloid-derived dimeric quaternary ammonium salts were prepared as chiral phase-transfer catalysts by the introduction of various functional groups on the phenyl ligand. Among them, the 2-F-substituted derivative 21 showed the highest enantioselectivity in the alkylation of the glycine anion equivalent 1 (97 to >99% ee).

New method for Hofmann rearrangement

Abstract Treatment of a series of primary aliphatic and aromatic carboxamides ( la - lm ) with NBS-Hg(OAc)2-ROH (A), dibromantin-Hg(OAc)2-ROH (B), NBS-AgOAc-ROH (C), or dibromantin-AgOAc-ROH (D) in DMF under argon provides corresponding carbamates ( 2a - 2m ) in nearly quantitative yields.

The highly enantioselective phase-transfer catalytic mono-alkylation of malonamic esters.

The phase-transfer catalytic alkylation of N,N-dialkylmalonamic tert-butyl esters in the presence of 1 mol% of (S,S)-3,4,5-trifluorophenyl-NAS bromide afforded highly enantioselective (S)-mono-alpha-alkylated products (up to 96% ee), which could be readily converted into versatile chiral building blocks without loss of chirality.

Enantioselective synthesis of (2R,3S)-(+)-catechin

Abstract A new enantioselective synthetic method for catechin from trans-methyl cinnamate derivative was developed via asymmetric dihydroxylation (ADH), the addition of an aryllithium species, followed by the Barton–McCombie reaction and an intramolecular Mitsunobu reaction as key steps.

Synthesis and antitumor activity of 7-substituted 20(RS)-camptothecin analogues

Novel water-soluble camptothecin analogues with excellent antitumor activity have been designed and synthesized by total synthesis. The analogues were evaluated for cytotoxic activity against five tumor cell lines. The most potent analogue 6c exhibited significant antitumor activity at wider range of doses as compared with camptothecin (T/C 243 % at 70mg/kg; T/C > 150% at 8.75–140mg/kg).