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Dianhydrohexitol azides dipolar 3+2 cycloaddition with N-arylmaleimides has been studied with NMR (1H and 13C, COSY, NOESY and HSQC) and X-ray analysis. In spite of low asymmetrical induction in this reaction, diastereomerically pure products have been obtained. These products are interesting over their structural similarity to griseolic acid derivatives and dihydropyrrolotriazoles, significant for pharmaceutics.

An appropriately substituted α-diazo β-keto ester, prepared from D-glucose, on treatment with a catalytic amount ot dirhodium tetraacetate gave a strained 1,5-dioxabicyclo[3.3.0]octane ring system with concomitant diastereoselective formation of a quaternary carbon substituted with both an ethoxycarbonyl group and a 2-ethoxy-2-oxoethyl group; the product is a key intermediate in the synthesis of a new griseolic acid analogue.

Starting from [14C] ethyl orthoformate and amidine derivative 3 derived from griseolic acid in 6 steps, the synthesis of [2-14C] griseolic acid 9′-(4-acetoxy-3-gethoxybenzyl)ester [14C]-2, a promising antiglaucoma agent with its regioisomer [2-14C] griseolic acid 8′-(4-acetoxy-3-gethoxybenzyl)ester 9 and [2-14C] griseolic acid [14C]-1 has been achieved.

Griseolic acid derivatives which were modified at the 2-and/or 6-positions were first synthesized from griseolic acid by a ring opening—reclosure reaction of the adenine ring. Among these derivatives, the 2-amino-6-deamino-6-hydroxyl (guanine) derivative showed 3.3 and 45 times stronger inhibitory activity against cAMP and cGMP PDE, respectively, than those of griseolic acid. Structure-activity relationships among these derivatives are also discussed.

Structure and biological activity of thirty-six new nucleoside antibiotics which appeared after the 1988 review are described. New synthetic analogs of neplanocin and oxetanocin are also described with special emphasis on their antiviral activities. New biosynthetic findings on nikkomycins, blasticidin S, and griseolic acid are also reviewed.

Griseolic acid, a potent inhibitor of cyclic adenosine 3',5'-monophosphate (cyclic AMP) phosphodiesterase (EC 3.1.4.17) was isolated from the cultured broth of Streptomyces griseoaurantiacus SANK 63479. Griseolic acid has an adenine moiety and two carboxyl groups and possesses the molecular formula C14H13N5O8. Griseolic acid inhibited cyclic AMP phosphodiesterase competitively with regard to cyclic AMP, the substrate and the resulting Ki value was 0.26 microM. Griseolic acid showed the most potent inhibitory effect on rat aorta cyclic AMP phosphodiesterase among the enzymes of several rat organs tested. The plasma level of cyclic AMP was increased when griseolic acid was subcutaneously injected rats.

(1. Intraocular pressure changes in albino rabbits after treatment with Gnseolic acid) Changes in intraocular pressure (IOP) were studied in albino rabbits with topical application and subconjunctival and mtravitreal injection of griseolic acid, a potent CAMP-phodphodiesterase inhibitor. Topical application of 0.5-1.99002riseolic acid showed no significant ocular hypotensive response. But, a significant reduction in IOP was observed at 2hr after topical application of 1-1.81308e-45riseolic acid. And the ocular hypotensive response lasted 5 hrs after topical application of 2-1.98092riseolic acid. IOP in rabbits was reduced m a dose-related manner following topical ocular application of concentrations of 0.526646061170 2%.0 Subconjunctival injection of 1 0x1.2f110b6a4b3ap-890nd 2 1.51394e-314riseolic acid also reduced IOP in rabbits significantly. A prolonged and marked decrease in IOP, lasting 5 days, followed the intravitreal injection of 1-1.98095riseolic acid. (2. Effect of gnseolic acid-ester on aqueous humor dynamics in rabbits) The mechanism of griseolic acid-ester (GA-ester), a potent CAMP-phosphodiesterase inhibitor, in lowering intraocular pressure (IOP) was studied using albino rabbits. The mean aqueous flow rate measured by fluorophotometry was significantly lower in GA-treated eyes than in control eyes. Topical application of GA-ester did not alter tonographic outflow or uveoscleal outflow measured using fluorescent isothiocyanate labeled-dextran. No differences in aqueous humor protein concentrations between GA-treated eyes and control eyes were observed. A GA-ester IOP lowering mechanism may be attributed to the decrease in aqueous inflow. Topical application of GA-ester does not induce an inflammatory response in the eye nor cause changes in the blood aqueous barners., Medicine

Griseolic acid inhibited cAMP phosphodiesterase (PDE) at low concentrations, the I50 being of the order of 0.01–0.1 μM. Administration of griseolic acid to rats increased the cAMP level in liver and plasma several-fold. It increased glycogen degradation in mouse liver and stimulated lipolysis in isolated rat fat cells. Griseolic acid did not block the adenosine-elicited accumulation of cAMP in guinea pig brain slices. It had no effect on cAMP-dependent protein kinase from rat liver nor on the adenyl cyclase from rat brain.

Griseolic acid, a potent inhibitor of cyclic adenosine 3', 5'-monophosphate phosphodiesterase, was isolated from the fermentation broth of Streptomyces griseoaurantiacus SANK 63479. Treatment of griseolic acid with HCl-MeOH gave adenine and pseudo-sugar. The structure of griseolic acid, adenine nucleoside type structure, was elucidated by chemical degradation and X-ray analysis, and was shown to be structure 1.

[第1報] 健常成熟白色家兎の片眼に,cAMP-phosphodiesterase阻害剤のひとつであるグリセオール酸(GA)の点眼,結膜下注射,硝子体内注入を行ない,非投与眼をコントロールとして,GAの眼圧下降効果について検討した。0.5-1.99002A(50μl)点眼では,わずかな眼圧下降しか得られなかったl-1.81308E-45A(50μl)点眼では,点眼後2時間の時点で,2-1.98092A点眼では,1～5時間後の時点で有意の限圧下降が得られた。処置眼と非処置眼の最大限圧差(Mean±SEM)は,0.5-1.81308E-45Aの点限では1.2±0.58mmHg, 1-1.81003E-45Aの点眼では2.0±0.57mmHg, 2-1.79935E-45Aの点眼では3.8±0.47mmHgとなり用量依存性の眼圧下降が認められた。1-1.01953E-45A(100μl)の結膜下注射では,注射後4時間と5時間の2時点で, 26.89979E-316A(100μl)の結膜下注射では,注射後3時間, 5時間および6時間の3時点で,処置眼の眼圧が有意に下降した。その最大眼圧差は1-1.81003E-45Aでは2.2±0.49mmHg,2-1.79661E-45Aでは2.9±1.04mmHgであった。14.8915E-270A(10μl)の硝子体内注入では,著明な眼圧下降が注射12時間後からみられ, 36時間持続した。注射48時間後に最も眼圧は下降(4.2±0.76mmHg)し,その後,眼圧は徐々に上昇して6日後に処置眼,非処置限問の眼圧差は無くなった。cAMP分解酵素,phosphodiesteraseの阻害剤であるGAの単独投与で,今回初めて有意の眼圧下降が得られたことを報告した。 [第2報] 白色家兎に,cAMP-phosphodiesterase阻害剤の一つであるグリセオール酸エステル(GAエステル)を投与し,その眼圧下降機序とGAエステル点限の血液房水関門に対する影車を検討した。フルオロフォトメトリー角膜法で求めた房水産生量は,GA処置限では2.63±0.27μl/min,対象眼では3.35±0.27μl/minとGA処置眼で有意に減少していた(p, (1. Intraocular pressure changes in albino rabbits after treatment with Gnseolic acid) Changes in intraocular pressure (IOP) were studied in albino rabbits with topical application and subconjunctival and mtravitreal injection of griseolic acid, a potent CAMP-phodphodiesterase inhibitor. Topical application of 0.5-1.99002riseolic acid showed no significant ocular hypotensive response. But, a significant reduction in IOP was observed at 2hr after topical application of 1-1.81308e-45riseolic acid. And the ocular hypotensive response lasted 5 hrs after topical application of 2-1.98092riseolic acid. IOP in rabbits was reduced m a dose-related manner following topical ocular application of concentrations of 0.526646061170 2%.0 Subconjunctival injection of 1 0x1.2f110b6a4b3ap-890nd 2 1.51394e-314riseolic acid also reduced IOP in rabbits significantly. A prolonged and marked decrease in IOP, lasting 5 days, followed the intravitreal injection of 1-1.98095riseolic acid. (2. Effect of gnseolic acid-ester on aqueous humor dynamics in rabbits) The mechanism of griseolic acid-ester (GA-ester), a potent CAMP-phosphodiesterase inhibitor, in lowering intraocular pressure (IOP) was studied using albino rabbits. The mean aqueous flow rate measured by fluorophotometry was significantly lower in GA-treated eyes than in control eyes. Topical application of GA-ester did not alter tonographic outflow or uveoscleal outflow measured using fluorescent isothiocyanate labeled-dextran. No differences in aqueous humor protein concentrations between GA-treated eyes and control eyes were observed. A GA-ester IOP lowering mechanism may be attributed to the decrease in aqueous inflow. Topical application of GA-ester does not induce an inflammatory response in the eye nor cause changes in the blood aqueous barners., 広島大学医学雑誌, 36(6), 683-689, 昭63-12月(1988); 広島大学医学雑誌, 38(1), 211-216, 平2-2月(1990)