Katsuo Unno

Magnetic microcapsules for targeted delivery of anticancer drugs

To achieve targeted distribution of anticancer drugs with sustained activity, ferromagnetic ethylcellulose microcapsules containing an anticancer drug, mitomycin C (FM-MMC-mc), were prepared by a method based on phase separation principles. Two prototypes of FM-MMC-mc were made: one with the drug as the core and zinc ferrite on its capsular surface (outer type); the other with both the drug and zinc ferrite as the core (inner type). Both preparations provided a sustained-release property and a sensitive response to conventional magnetic force, although certain differences in the release rate of drug, magnetic responsiveness, and particle size were found between the two dosage forms. Animal studies showed that the magnetic microcapsules could be magnetically controlled in the artery and urinary bladder. VX2 tumors in the rabbit hind limb and urinary bladder were successfully treated with magnetic control of FM-MMC-mc. Pharmacokinetic study revealed that the targeting of the microcapsules markedly enhanced the drug absorption into the surrounding tissues for a prolonged period of time. The results indicate the feasibility and effectiveness of the magnetic microcapsules as a targeted drug delivery system.

Colonic mucosa-specific “pro-antedrugs” for oral treatment of ulcerative colitis: design, synthesis and fate of methyl 20-glucopyranosyloxyprednisolonates

Abstract Hydrophilic steriod derivatives, methyl 20-β-glucopyranosyloxyprednisolonates (15 and 16), were synthesizd from prenisolone via methyl 20( R/S )-dihydroprednisolonates (2 and 1) based on a novel colonic mucosa-specific drug delivery system. Optimal conditions for the syntheses of each isomer 1 and 2 were found by the extensive studies on the reaction rates from prednisolone under various concentrations of cupric acetate in dry methanol. Their configurations at C-20 in compounds 1 and 2 were determined by their formation mechanism. The fate of compounds 15 and 16 after the oral administration was examined in rats ang guinea-pigs. The glycosides were stable in the small-intestinal contents, but the glycoside bonds were cleaved by the action of bacteria in the large-intestinal contents to release compounds 1 and 2, respectively, which were rapidly hydrolysed to the inactive carboxylates in the plasma. The high recovery of the glycosides and the aglycons in the large-intestinal contents after intrajejunal administration of compounds 15 and 16 may be orally effective ‘pro-antedrugs’, which specifically express the anti-inflammatory acitivity in the glycosides 15 and 16 may be orally effective ‘pro-antedrugs’, which specifically express the anti-inflammatory activity in the colonic mucosa with no systemic effect.

Enantioselective route to (–)-chokol A

Stereoselective introduction of a methyl group to (3R)-2-methylcyclopentanone (2), followed by orthoester Claisen rearrangement provided the methyl ester (6) leading to (–)-chokol A (4).

Highly enantioselective synthesis of (-)-chokol A

Stereoselective introduction of a methyl group into the (3S)-2-methylcyclopentanone 3, followed by Claisen rearrangement of the vinyl ether 10 derived from the allyl alcohol 7 provided separable methyl esters 6a and 6b. Reduction of 6a and subsequent homologation of the side-chain afforded the pivaloyl ester 16 after protection of the primary alcohol 15 with pivaloyl chloride. Cleavage of the double bond of compound 16, followed by sodium borohydride reduction of the resultant aldehyde 17, produced a mixture of the diols 18 and 19 leading to (–)-chokol A 5. Its enantiomeric excess was determined based on examination of the 1H NMR spectrum of its MTPA ester 25.