Josef Fried

2,2-Difluoro-3-hydroxyesters by Reformatskii reaction

Abstract Ethyl bromodifluoroacetate undergoes facile Reformatskii addition to aldehydes and ketones to form 2,2-difluoro-3-hydroxyesters.

Synthetic derivatives of cortical hormones.

Publisher Summary Interest in studying the effects of structural modification of the naturally occurring steroid hormones upon activity has been evident ever since the elucidation of the structure of the sex hormones in the early 1930s. Emphasis on this particular field of steroid research was the result, first, of a natural curiosity to determine the chemical features essential for the complex hormonal activities of androgens, estrogens, and progestagens, and, secondly, of the very practical consideration of obtaining more desirable agents at lower cost for use in both human and veterinary medicine. Some of the features considered desirable for this purpose were, and still are, peroral effectiveness, high potency, extended duration of action, the separation of anabolic from androgenic and of gonadotropininhibiting from estrogenic activity. It soon became evident that, with the exception of the estrogens, the steroidal sex hormones are highly specific in their dependence of activity upon structure, and that only a limited number of structural variations would result in the retention of any biological activity, not to speak of increases in potency or separation of the physiological components involved.

Morphine-3-Succinyl—Bovine Serum Albumin: An Immunogenic Hapten-Protein Conjugate

Morphine-3-hemisuccinate was synthesized by reaction of morphine with succinic anhydride. This compound was conjugated to bovine serum albumin by the mixed anhydride method, and the degree of conjugation was determined by base hydrolysis of the conjugate, extraction, and measurement of free morphine. An average of 6.5 molecules of morphine were conjugated to each molecule of protein. Eleven rabbits immunized with varying doses of the conjugate were producing antibody 8 weeks later, as determined by a modification of the ammonium sulfate method, which measures primary binding of antigen by antibody.

SYNTHESIS AND BIOLOGICAL ACTIVITY OF PROSTAGLANDINS AND PROSTAGLANDIN ANTAGONISTS

A t a p r e v i o u s symposium on p r o s t a g l a n d i n s w e r e p o r t e d on a group of p r o s t a g l a n d i n ana logs i n which t h e 7-methyle n e group i s r e p l a c e d by o x y g e n ( F r i e d e t a 1 , 1 9 6 7 ) . During t h e i n t e r v e n i n g t h r e e y e a r s t h e b i o l o g i c a l p r o p e r t i e s of some of t h e s e s u b s t a n c e s have been e x p l o r e d ( F o r d & F r i e d , 1 9 6 9 ; F r i e d e t a1,1969a) , and t h e r e s u l t s o b t a i n e d have s e r v e d t o d i r e c t ou r s y n t h e t i c work i n t o t h r e e main a r e a s , namely, t h e s y n t h e s i s of 7-oxa-PGFia ( F r i e d e t a1,1968,1969a) and 7-oxa-PGEl(Fried e t a 1 , 1 9 7 0 ) , t h e s y n t h e s i s of 5and 13oxa a n a l o g s and t h e r e s o l u t i o n of t h e e n a n t i o m e r i c m i x t u r e s o b t a i n e d p r e v i o u s l y . Furthermore, t h e r e a c t i o n s e l a b o r a t e d d u r i n g t h e above s t u d i e s have been employed toward t h e synt h e s i s of t h e p r o s t a g l a n d i n s themse lves .

Comparison of substrate specificities of the human placental NAD- and NADP-linked 15-hydroxyprostaglandin dehydrogenases

A study of the relative activity of the purified placental NAD- and NADP-linked 15-hydroxyprostaglandin dehydrogenases with various prostaglandins and thromboxane B2 (TxB2) suggests that most, if not all, oxidation in the placenta of the 15-hydroxyl group of prostaglandins of the A, E, and F series as well as PGI2 (prostacyclin) and 6-keto PGF1 alpha is catalyzed by the NAD-linked enzyme. Prostaglandin B1 is an excellent substrate for the NADP-linked enzyme. Despite the conformational similarities between PGB1 and PGI2, the latter molecule is a poor substrate for the NADP-linked enzyme. Thromboxane B2 is not oxidized by the NAD-linked enzyme and is oxidized slowly by the NADP-linked enzyme.

Synthesis and pheromonal properties of (Z)-7,7-difluoro-8-dodecenyl acetate a difluoro derivative of the sex pheromone of the oriental fruit moth

Abstract 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.

Synthesis of multistriatin enantiomers and their action onScolytus multistriatus (Coleoptera:Scolytidae)

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.

Separation of Acetylenic Prostaglandin Isomers as Cobalt Complexes

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

Immunochemical studies of opioids: Specificities of antibodies against codeine and hydromorphone☆

Abstract Two new immunogenic opioid-protein conjugates were prepared. Codeine-6-hemisuccinate was synthesized from the reaction of codeine with succinic anhydride and hydromorphone-6-carboxymethyloxime was synthesized from the reaction of hydromorphone with α-aminoxyacetic acid. Both opioids were attached covalently to bovine serum albumin using the mixed anhydride procedure and employed as immunogens in rabbits. Antibody measured by the ammonium sulfate method showed increases in titer and avidity following subsequent immunizations. The specificities of both antisera were studied by competitively inhibiting the binding of labeled opioid to antibody by the prior addition of increasing concentrations of various unlabeled opioids. The ranges of immunoreactivity of both antisera were different and corresponded closely to the structures of the respective immunizing haptens. These observations suggest that antibodies prepared against codeine, hydromorphone, and morphine may be used in combination for qualitative as well as quantitative determinations of opioids in biologic fluids.

A novel synthesis of the cyclic carbinolamide moiety of the maytansinoids

Abstract The α-diketo urethane 3 cyclizes to form the cyclic carbinolamide 4 using TMS triflate and 2,6-di- t -butylpyridine. The siloxy group of 4 is readily exchanged in methanol or water to form 6 or 7 . Remarkably, 3 does not cyclize spontaneously or on standard acid catalysis.