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Functionalized 2-alkyl derivatives of inosinic acid have been synthesized to serve as reversible as well as irreversible inhibitors of the human type II enzyme inosine monophosphate dehydrogenase. These compounds were designed to react with Cys-331 of the enzyme to form covalent bonds so as to interfere with the normal enzyme mechanism which involves attack of Cys-331 at C-2 of the substrate. Mass spectrometric analysis of the reaction products after enzymatic degradation confirmed the appropriateness of the inhibitor design.

A short and practical synthesis of 2-vinylinosine from readily available materials is described.

The synthesis of the TXA 2 /PGH 2 receptor antagonist 6 ([7,7-difluoro-3-[(N-heptanoylglycyl)aminomethyl-2,6-dioxabicyclo[3.1.1]hept-4-yl]-5-heptenoic acid )from the known chiral intermediate (-)-8 is described. The critical reaction is the inversion of C-S in 11a and 11b by an intramolecular cyclization reaction induced by nucleophilic reagents as shown in structure 13a. The key intermediate 22 was prepared in 26.5% yield in five steps. Diastereoselectivity is high in all but one of the steps, the Reformatsky reaction, which leads to equal amounts of 11a and 11b. The design of 6 is based on the dioxabicycloheptane nucleus characteristic of TXA 2 (1), which has been stabilized by fluorination. To this nucleus the two side chains are attached in cis orientation, and the ω-chain is modified as reported for the receptor antagonist (-) 5, which in turn is an analogue of PGH 2 (3). These changes inthe side chains have the effect of converting the powerful agonist 2 (DFTXA 2 ) into a receptor antagonist devoid of agonist activity, which binds to the receptor with nanomolar affinity. These findings lend support to the view of a single TXA 2 /PGH 2 receptor

The high enantio- and regiospecificity reported from this laboratory for the hydrolysis of the diacetate (±)-2 with pig liver esterase to yield enantiomericly pure monoacetate (+)-3a has been investigated further to define some of the structural features responsible for this unusual degree of specificity. The hydrolysis of the isomeric (±)-5 was found to proceed with identical specificity both qualitatively and quantitatively, indicating that the enzyme recognizes the overall geometry of these substrates but is unable to distinguish between the CF 2 group and the oxygen bridge.Partial hydrolysis of a monocyclic diacetate showed parallel enantioselectivity but proceeded with only 25% ee.It is concluded that conformationally stable molecules may offer favorable targets for regio and/or enantioselectivity in PLE reactions

The synthesis of the TXA 2 /PGH 2 receptor antagonist 6 ([7,7-difluoro-3-[(N-heptanoylglycyl)aminomethyl-2,6-dioxabicyclo[3.1.1]hept-4-yl]-5-heptenoic acid )from the known chiral intermediate (-)-8 is described. The critical reaction is the inversion of C-S in 11a and 11b by an intramolecular cyclization reaction induced by nucleophilic reagents as shown in structure 13a. The key intermediate 22 was prepared in 26.5% yield in five steps. Diastereoselectivity is high in all but one of the steps, the Reformatsky reaction, which leads to equal amounts of 11a and 11b. The design of 6 is based on the dioxabicycloheptane nucleus characteristic of TXA 2 (1), which has been stabilized by fluorination. To this nucleus the two side chains are attached in cis orientation, and the ω-chain is modified as reported for the receptor antagonist (-) 5, which in turn is an analogue of PGH 2 (3). These changes inthe side chains have the effect of converting the powerful agonist 2 (DFTXA 2 ) into a receptor antagonist devoid of agonist activity, which binds to the receptor with nanomolar affinity. These findings lend support to the view of a single TXA 2 /PGH 2 receptor

A short and practical synthesis of 2-vinylinosine from readily available materials is described.

The author's recollections of the events leading to the first synthesis of the 9α-fluorosteroids at Squibb, the further development of this discovery and its influence on the steroid industry are presented.

A synthesis of allylic difluorides is described, exemplified by the preparation of the title compound, which was shown to elicit the biological responses characteristic of (Z)-8-dodecenyl acetate, the pheromone of the Oriental fruit moth. It is concluded that the geometry of the double bond rather than its chemical reactivity is essential for biological activity.

The cis-trans isomerization of 1 by Br2 in CCl4 is described. A bridged bromonium cation α to CF2 is destabilized resulting in a carbocation bromide ion pair at the β-carbon capable of free rotation and loss of bromine to form 2 . A CF2 group appears to be more effective in promoting isomerization than aryl in the case of stilbenes.

Irradiation of the difluorovinyl ether aldehyde 6 yields the tricyclic products 7 and 8 and the bicyclic dioxepene 9. There was no evidence for the formation of the isomeric [3.1.1] structure 1 containing the ring system of thromboxane A2.

A pheromone mixture containing enantiomerically pure (−)-α-multistriatin of known absolute configuration prepared by total synthesis was found to be as attractive as the natural pheromone to the smaller European elm bark beetle,Scolytus multistriatus, a vector of Dutch elm disease. Its (+)-enantiomer, on the other hand, was no more active than controls in both laboratory and field tests, and at high levels it appeared to inhibit the response to the (−)-enantiomer.

The effects of 7-oxa-13-prostynoic acid (7-OPA), alone and as an antagonist of PGE2 and PGF2α, were investigated in isolated rabbit aortic and canine renal arterial (diameter ∼0.5 mm) strips. 7-OPA caused contractions in both preparations; threshold concentrations were 3-to 10-fold higher than the PGs and maximum contraction was 50-60%. In concentrations of 10–5 M, 7-OPA inhibited contractions by PGF2α and PGE2. The same concentration of 7-OPA did not inhibit norepinephrine-induced contractions. These data indicate that 7-OPA is a partial agonist of PG receptors and produces its antagonism of PGE2 and PGF2α by that mechanism.

Six glutathione-containing inhibitors of the human NADP-linked 15-hydroxyprostaglandin dehydrogenase have been isolated from placental homogenates. Glutathione disulfide is one of these inhibitors. Although the structures of the other five have not been fully elucidated, all are disulfides. Studies with these compounds and with other mixed disulfides have shown that the glutathione mixed disulfides of beta-mercaptopyruvate, mercaptoacetate, and beta-mercaptolactate are more effective inhibitors of the enzyme than are the glutathione-containing mixed disulfides isolated from placental homogenates. beta-Mercaptolactate is particularly noteworthy because of its low Ki (0.13 microM). The results reported here suggest that the activity of the prostaglandin dehydrogenase may be influenced in vivo by various glutathione mixed disulfides.

A synthesis of allylic difluorides is described, exemplified by the preparation of the title compound, which was shown to elicit the biological responses characteristic of (Z)-8-dodecenyl acetate, the pheromone of the Oriental fruit moth. It is concluded that the geometry of the double bond rather than its chemical reactivity is essential for biological activity.

The escape of the blastocyst from the zona pellucida in vitro is probably the result of expansion due to fluid accumulation in the blastocoele. This fluid accumulation is mediated by the epithelial trophectoderm. Since prostagiandins of the E series are involved in the control of water movement across epithelia, the effect of prostaglandin antagonists on the hatching of mouse blastocysts has been examined. Protein-free culture media have been used to overcome the complicating effects of protein bindings of the drugs on their activities. 7-Oxa- 13-prostynoic acid, meclofenamic acid, indomethacin and pheniodone inhibit hatching, but the properties of their dose-response lines vary. 7-Oxa-1 3-prostynoic acid and meclofenamic acid have steep dose-response lines. The median inhibitory doses (lD5Os) and confidence limits (P =0.05) are: 7-oxa-13-prostynoic acid 0.81 MM (0.55-1.20); meclofenamic acid 7.72 MM (3.43-17.4). Indomethacin and phenidone have very flat dose-response lines indicating wide variability of response. The ID5Os and the confidence limits are: indomethacin 9.08 �M (1-67); phenidone 20MM (92-263). Thus, 7-oxa-13-prostynoic acid has much greater activity than the other three compounds. The results provide circumstantial evidence that endogenous prostaglandins are involved in blastocyst expansion and may play a role in the process of implantation. Interference with blastocyst expansion with antiprostaglandins administered in a medicated I.U.D. may be a useful means of contraception.

Synthese a partir de la reaction d'(alcynyl trialkylsilyl) ethers avec le ([difluoro-4,4 iodo-4 butyne-2 yl] [perhydro pyrannyl-2]) ether en presence de butyl-lithium

Previously inseparable acetylenic prostaglandins have been separated as their cobalt complexes. This methodology appears to be of broader utility.

Recent biological studies of 9-alpha-halo-11-oxygenated progesterones and of their 12-alpha-halogenated analogues outside of the corticoid area have resulted in the discovery of their antiuterotrophic and progestational properties. Adrenocorticoid activity of 9-alpha- and 12-alpha-haloprogesterones data have shown the gradual increase in glycogenic activity with decreasing atomic weight of the halogen atom. In the case of the sodium retention assay only the fluorinated derivatives show pronounced activity the activity of the remaining members of the series being negligible. The most quantitative parallelism of the activities of the 9-alpha- and 12-alpha-halo derivatives has served to support the hypothesis that the activity-enhancing properties of the halogen atom are a function of the latters electonegativity. Huggens and Jensen were the first to show that 9-alpha-halogenation of 11-oxygenated steroids could enhance potency outside of the corticoid area. In determining the inhibition of growth of the uterus by 9-alpha-fluorinated steroids it was shown that 9-alpha-fluorination enhanced the biological activity of the parent substance. Hertz and Tullner using the Clauberg technique were able to demonstrate classic progesteronelike activity for 9-alpha-steroids. In an effort to ascertain the effects of the different halogens on antiuterotrophic and progestational activity studies were extended to include all the 9-alpha- and 12-alpha-halo 11-beta-hydroxyprogesterones and 11-ketoprogesterones. In comparing the potencies of the various derivatives it was evident that the structure-activity relationships established for corticoid activity no longer obtained in this case. Turning to the progestational data obtained in the Clauberg assay it is noted that in contrast to progesterone itself this group of substances possesses activity when administered by both the parenteral and oral routes. Opposing trends in the structure-activity relationships in animals permit the selection of 9-alpha-bromo-11-ketoprogesterone as the most suitable agent for exploration of its progestational activity in man.

A new tetracyclic triterpenoid acid, sulphurenic acid, has been isolated from the mycelium of the fungus Polyporus sulphureus grown in both surface and submerged culture, and its structure determined as 15α-hydroxyeburicoic acid (II). It represents 25% of the total steroid content of P. sulphureus , the remaind erbeing eburicoic acid. Ergosterol has been isolated from the lipid fraction of this fungus.