Synthesis of ring halogenated prostaglandins (1)

The synthesis of nine mono- and difluoro prostaglandins , , , , , , and , and two monochloro prostaglandins and , from appropriately protected derivatives of natural PGF₂ is described.     

Synthesis of lower chain allenic prostaglandins (1)

The synthesis of four lower chain allenic prostaglandin F_α analogues IXA-D is described.The allenyl moiety has only occasionally been incorporated into the prostanoid skeleton and in all the examples thus far reported ·(2,3), this functionality is located in the upper side chain at carbons 4–6. This communication describes the synthesis of four isomeric allenyl PGF_α derivatives wherein the cumulated diene system is situated at positions 13–15.     

Synthesis of (19R)-19-hydroxy-PGE and -PGF prostaglandins

We wish to report here the total synthesis of the naturally occurring (19R)-19-hydroxy-prostaglandins of the PGE and PGF series.     

Prostaglandins V (1). Synthesis and pharmacology of (±)-11-deoxy-10-hydroxyprostaglandin E1 methyl ester

(±)-11-Deoxy-10-hydroxy-PGE₁ methyl ester (Va) has been synthesised conjugate addition of the cuprate (III) to the 5-tetrahydropyranyloxycyclopentenone (IId).Va was found to be 0.1 times as active as PGE₁ as a uterine stimulant in the anaesthetized pregnant rat, 0.25 times as active as PGE₁ in causing vasodepression in the anaesthetized cat, and approximately equiactive to PGE₁ in inducing bronchoconstriction.     

Synthesis and antifertility activity of ω-chain phenyl- and 16-phenoxy-analogues of (±)-11-deoxyprostaglandin F1α

Some ω-chain phenyl- and 16-phenoxy- analogues of (±)-11-deoxyprostaglandin F_1α have been synthesized and evaluated for anti-fertility activity in the hamster. 11-Deoxy-16-phenoxy-17,18,19,20-tetranor-PGF_1α was the most active member of the series with an ED₅₀ equal to that of PGF_2α. 11-Deoxy-17-phenyl-18,19,20-trinor-PGF_1α, which was one third as active as PGF_2α, was more potent than the corresponding 16- and 18-phenyl compounds. Aryl ring substitution was found to lower activity, except that with the 16-phenyl compound, p-bromo and m-trifluoromethyl substitution increased the potency.The antifertility activity of the phenoxy compounds, which were poor substrates for 15-hydroxyprostaglandin dehydrogenase, was shown to correlate well with the binding affinity for the bovine corpus luteum PGF_2α receptor. Some quantitative structure-activity data supporting this finding are presented.     

Synthesis and biological activity of 2-decarboxy-2-(tetrazol-5-yl)prostaglandins

The synthesis of 2-decarboxy-2-(tetrazol-5-yl)prostaglandins of the E₁, E₂, F₁α and F₂α series is described together with their biological effects on gerbil colon smooth muscle and rat blood pressure.     

Synthesis and biological activities of octyl 2,3-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2-O-sulfo-alpha-L-fucopyranosyl-(1-->4)-2,3-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2-O-sulfo-alpha-L-fucopyranosyl-(1-->4)-2,3-di-O-sulfo-beta-L-fucopyranoside

Octyl 2,3-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2-O-sulfo-alpha-L-fucopyranosyl-(1-->4)-2,3-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2-O-sulfo-alpha-L-fucopyranosyl-(1-->4)-2,3-di-O-sulfo-beta-L-fucopyranoside, a fucosyl pentasaccharide with a regular structure resembling the repeating unit of a natural sulfated fucan, was chemically synthesized using a convergent '2+3' strategy. Regioselective 3-O-silylation of beta-thiofucopyranoside and AgOTf-catalyzed glycosylation of the protected glycosyl trichloroacetimidate facilitated a one-pot trisaccharide synthesis. The synthesized target compound showed good antitumor activity in vivo, and promising anticoagulant activity in vitro.     

Synthesis and biological activity of 2-decarboxy-2-(tetrazol-5-yl)prostaglandins

The synthesis of 2-decarboxy-2-(tetrazol-5-yl)prostaglandins of the E₁, E₂, F₁α and F₂α series is described together with their biological effects on gerbil colon smooth muscle and rat blood pressure.     

Lipase Catalyzed Resolution of (±)-2-Substituted 1-Propanol Derivatives Possessing an Aromatic Ring

For the purpose of the chiral synthesis of natural products, lipase-catalyzed kinetic resolutions of three types of 2-substituted 1-propanol derivatives (each having an aromatic ring) was investigated. In every case, chiral recognition of the primary alcohol unit took place to provide the corresponding alcohols and the acetates in high optical purity. The (2S,3S)-5-aryl-2-methyl-3-hydroxy-4E-pentenol 5 was formally converted into the antibiotic, (-)-oudemansin X.     

Synthesis and biological activities of octyl 2,3,4-tri-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-beta-L-fucopyranoside

An efficient method for the regioselective 3-O-silylation of beta-thiofucopyranoside was disclosed. Based on this discovery, we described a high-yielding strategy for the synthesis of the natural core structure of L-fucan and its fully sulfated derivative. The bioassay suggested that octyl 2,3,4-tri-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-beta-L-fucopyranoside presented better antitumor activities than that of the free tetramer based on Sarcoma 180 cells and Lewis lung carcinoma model studies.     

Synthesis and lipase-catalyzed resolution studies on novel (±)-2-(2-acetoxyethyl)-4-arylmethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylates

Five novel methyl (±)-2-(2-acetoxyethyl)-4-arylmethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylates have been synthesized and their lipase-catalyzed resolution via stereoselective deacetylation of acetoxyethyl moiety present in the molecule studied. It has been observed that Novozyme^®-435 in THF efficiently catalyses the enantioselective deacetylation of these acetoxyethyl dihydrobenzoxazines leading to the formation of optically enriched methyl (+)-4-arylmethyl-2-(2-hydroxyethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylates. The biocatalytic reaction was found to be chemoselective alongwith being enantioselective, because the lipase exclusively catalyses the deesterification of the ester function derived from the alcoholic hydroxy moiety in the molecule over the one derived from the aromatic carboxylic acid group.     

Synthesis of (R)-2,3-epoxypropyl(1-->3)-beta-D-pentaglucoside

The title pentasaccharide was synthesized via a 2+3 strategy. The disaccharide donor, 3-O-acetyl-2-O-benzoyl-4,6-O-benzylidene-beta-D-glucopyranosyl-(1-->3)-2-O-benzoyl-4,6-O-benzylidene-alpha-D-glucopyranosyl trichloroacetimidate (8), was obtained by selective coupling of allyl 2-O-benzoyl-4,6-O-benzylidene-alpha-D-glucopyranoside with 3-O-acetyl-2-O-benzoyl-4,6-O-benzylidene-alpha-D-glucopyranosyl trichloroacetimidate (4), followed by deallylation, and trichloroacetimidation. Meanwhile, the trisaccharide acceptor, allyl 2-O-benzoyl-4,6-O-benzylidene-beta-D-glucopyranosyl-(1-->3)-2-O-benzoyl-4,6-O-benzylidene-beta-D-glucopyranosyl-(1-->3)-2-O-benzoyl-4,6-O-benzylidene-beta-D-glucopyranoside (12), was prepared by coupling of allyl 2-O-benzoyl-4,6-O-benzylidene-beta-D-glucopyranosyl-(1-->3)-2-O-benzoyl-4,6-O-benzylidene-beta-D-glucopyranoside with 4, followed by deacetylation. Condensation of 8 with 12, followed by epoxidation, and deprotection, gave the target pentaoside.     

Chemo-enzymatic synthesis of (R)-(+)-aminoglutethimide by kinetic resolution of (±)-4-cyano-4-phenyl-1-hexanol

Chemo-enzymatic approaches for the synthesis of the family of aromatase inhibitory drug via lipase-catalyzed kinetic resolution of (±)-4-cyano-4-phenyl-1-hexanol (2) as appropriate precursors were described. Enzymatic transesterification of primary alcohol (±)-2 using Pseudomonas cepacia (Amano PS, PCL) provided the enantiopure alcohol (R)-(−)-2 with 99% ee at conversion of 86%, while that of (±)-2 using Pseudomonas fluorescens (Amano AK, LAK) provided the (S)-(+)-2 with 96% ee at conversion of 86%. Chemical transformation of substrate (R)-(−)-2 gave (R)-(+)-aminoglutethimide (1) in enantioselectively high yield.     

Synthesis of α-(S)- acylamino-n-(hydroxydioxocyclobutenyl)- γ-lactams

Monocyclic γ - lactams 2, activated by a hydroxycyclobutenedione moiety have been prepared from (L)-N^tBoc-glutamine, as potential antibacterial agents.     

Enantioselective hydrolysis of (±)-chloramphenicol palmitate by hydrolases

(±)-Chloramphenicol palmitate has been efficiently resolved by enantioselective hydrolysis in organic medium in the presence of Rhizopus sp. lipase affording the palmitate of RR-chloramphenicol and SS- chloramphenicol in high chemical and enantiomeric yields.     

Mechanistic aspects of rearrangement of 16alpha-hydroxy-17-keto steroids to the 17beta-hydroxy-16-keto isomers

The mechanistic aspects of the alkali-catalyzed rearrangement of 16alpha-hydroxy-17-keto steroid 1 to 17beta-hydroxy-16-keto steroid 2 are elucidated by use of (18)O- and deuterium-labeling experiments. The (18)O-labeling experiments refute the gem-hydration-quasi-diaxial dehydration mechanism for the rearrangement previously proposed and support the conventional enolization mechanism. Moreover, equilibrium by gem-hydration-dehydration occurs at the C-17 carbonyl more efficiently than at the C-16 carbonyl. Enolization rate of a carbonyl group at C-16 of 17beta-ketol 2 toward the C-17 position (k(16,17)) was about 8-10 times higher than those of 16alpha-ketol 1 toward the C-16 position (k(17,16)) and ketol 2 toward the C-15 position (k(16,15)). The marked deuterium-isotope effect on each enolization was observed with k(H)/k(D) ranging between 5.4 and 8.8. The present findings reveal that the initial hydration-dehydration equilibration at the C-17 carbonyl of ketol 1 followed by enolization of the carbonyl gives the ene-diol intermediate that isomerizes quantitatively to the 16-keto isomer of which the 16-carbonyl moiety enolizes preferentially toward the C-17 position rather than the C-15 position, yielding the ene-diol. Computational calculations of ground state energies of ketols 1-M and 2-M, trans-cyclohexane/cyclopentane structures, and their activation energies in the rearrangement support the dynamic aspects of the rearrangement as well as the kinetics data of the enolization.     

Biological activity and antidiabetic potential of synthetic fragment peptides of glucose-dependent insulinotropic polypeptide, GIP(1-16) and (Pro3)GIP(1-16)

Glucose-dependent insulinotropic polypeptide (GIP) is a key physiological insulin releasing peptide and potential antidiabetic agent. The present study was undertaken in an attempt to develop small molecular weight GIP agonist and antagonist molecules. The bioactivity of two modified C-terminally truncated fragment GIP peptides, GIP(1-16) and (Pro3)GIP(1-16), was examined in terms of insulin secretion and glucose homeostasis using BRIN-BD11 cells and type 2 diabetic mice. In vitro insulin release studies demonstrated that GIP(1-16) and (Pro3)GIP(1-16) possessed weak GIP-receptor agonist and antagonistic properties, respectively. Intraperitoneal administration of GIP(1-16) in combination with glucose to obese diabetic (ob/ob) mice did not effect the glycaemic excursion and had a marginal effect on insulin release. GIP(1-16) was substantially less effective than the native GIP(1-42). (Pro3)GIP(1-16) administration significantly curtailed (P < 0.05) the insulinotropic and glucose lowering effects of native GIP, but was significantly less effective than (Pro3)GIP. Based on the established concept of a therapeutic benefit of GIP receptor antagonism in obesity-diabetes, ob/ob mice received once daily injection of (Pro3)GIP(1-16) for 14 days. No significant effects were observed on food intake, body weight, HbA1c, glucose tolerance, metabolic response to feeding and either insulin secretion or insulin sensitivity following prolonged (Pro3)GIP(1-16) treatment. These data demonstrate that C-terminal truncation of GIP or (Pro3)GIP yields small molecular weight GIP molecules with significantly reduced biological activity that precludes therapeutic utility.