Several Z-and E-methylenecyclopropane nucleoside analogues were synthesized and evaluated for antiviral activity. Reaction of the Z-and E-2-amino-6-chloropurine methylenecyclopropanes with ammonia or cyclopropylamine gave 2,6-diamino or 2-amino-6-cyclopropylamino analogues. Alkylation elimination of N 4 -acetylcytosine with ethyl Z-and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave a mixture of the Zand E-methylenecyclopropane derivatives of cytosine. Reduction furnished a mixture of syncytol and the E isomer. Benzoylation led to the respective N 4 -benzoyl derivatives which were separated by chromatography. Debenzoylation afforded pure syncytol and the E isomer. Alkylation of 2,4-bis-O-trimethylsilylthymine with ethyl Z-and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave the corresponding Z-and E-1-bromocyclopropylmethylderivatives of thymine. Basecatalysed elimination of HBr gave Z-and E-methylenecyclopropane carboxylic esters. Reduction furnished, after chromatographic separation, synthymol and the E isomer. The Z/E isomeric assignment of the obtained products followed from 1 H NMR spectroscopy. The methylenecyclopropane analogues were tested for antiviral activity in vitro against human and murine cytomegalovirus (HCMV, MCMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), hepatitis B virus (HBV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1). The Z-2-amino-6-cyclopropylaminopurine analogue was the most effective agent against HCMV (EC 50 or EC 90 0.4-2 µM) followed by syncytol and the Z-2,6-diaminopurine analogues (EC 50 or EC 90 3.4-29 and 11-24 µM, respectively). The latter compound was also a strong inhibitor of MCMV (EC 50 0.6 µM). Syncytol was the most potent against EBV (EC 50 <0.41 and 2.5 µM) followed by the Z-2,6-diaminopurine (EC 50 1.5 and 6.9 µM) and the Z-2-amino-6-cyclopropylaminopurine derivative (EC 50 11.8 µM). Syncytol was also most effective against VZV (EC 50 3.6 µM). Activity against HSV-1, HSV-2 and HHV-6 was generally lower; synthymol had an EC 50 of 2 µM against HSV-1 (ELISA) and 1.3 µM against EBV in Daudi cells but was inactive in other assays. The 2-amino-6-cyclopropylamino analogue displayed EC 50 values between 215 and >74 µM in HSV-1 and HSV-2 assays. 2-Amino-6-cyclopropylaminopurine and 2,6-diaminopurine derivatives were effective against HBV (EC 50 2 and 10 µM, respectively), whereas none of the analogues inhibited HIV-1 at a higher virus load. Syncytol and the E isomer were equipotent against EBV in Daudi cells but the E isomer was much less effective in DNA hybridization assays. The E-2,6-diaminopurine analogue and E isomer of synthymol were devoid of antiviral activity.

A series of R and S enantiomers of 2-aminopurine methylenecyclopropane analogues of nucleosides was synthesized. Two diastereoisomeric lipophilic phosphate prodrugs derived from R and S enantiomers of 2,6-diaminopurine analogue were also prepared. Enantioselectivity (diastereoselectivity in case of prodrugs) of in vitro antiviral effects was investigated with human and murine cytomegalovirus (HCMV and MCMV, respectively), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2, respectively), human immunodeficiency virus type 1 (HIV-1), hepatitis B virus (HBV), Epstein-Barr virus (EBV) and varicella zoster virus (VZV). Strong differences in enantioselectivity were found between the R and S enantiomers of adenine analogue and enantiomeric 2-aminopurine analogues. Thus, the enantiomers of adenine analogue were equipotent against HCMV but not MCMV, where the S enantiomer is strongly preferred. The same S preference was found throughout the 2-aminopurine series for both HCMV and MCMV. In contrast, R-synadenol in HIV-1 assays was the best agent, whereas the S enantiomers of moderately effective 2-amino-6-cyclopropylamino and 2-amino-6-methoxypurine analogues were preferred. Little enantiomeric preference was found for R and S enantiomers of synadenol and the corresponding enantiomers of 2,6-diaminopurine analogue against HBV. A mixed pattern of enantioselectivity was observed for EBV depending on the type of host cells and assay. Against VZV, the R and S enantiomers of adenine analogue were equipotent or almost equipotent, but throughout the series of 2-aminopurine analogues a distinct preference for the S enantiomers was found. The stereoselectivity pattern of both diastereoisomeric prodrugs mostly followed enantioselectivity of the parent analogues. The varying enantioselectivities in the series of purine methylenecyclopropane analogues are probably a consequence of differences in the mechanisms of action in different virus/host cell systems.

Extracts of two species of marine algae, Constantinea simplex and Farlowia mollis , were tested for antiviral activity in tissue culture and in experimental infections of mice. Treatment of confluent mouse embryo fibroblast cell monolayers with either compound before viral inoculation was effective in inhibiting the replication of herpes simplex virus type 1 and type 2, vaccinia virus, and vesicular stomatitis virus, but not encephalomyocarditis virus, Semliki Forest virus, or murine cytomegalovirus. Prophylactic administration of these extracts was effective in reducing final mortality or prolonging the mean day of death of animals inoculated by the intraperitoneal, intracerebral, or intranasal routes with herpes simplex virus type 2. When therapy was initiated after viral inoculation or at a site other than that of viral inoculation, no significant effect on mortality or on mean day of death was observed. Neither preparation was effective in mice inoculated intraperitoneally with encephalomyocarditis virus, Semliki Forest virus, or murine cytomegalovirus or in animals infected intravaginally with herpes simplex virus type 2. The prophylactic but not therapeutic antiviral activity of these preparations seriously limits their potential use in human herpes simplex virus infections.

The glycosylation of 3,4-dicyano-2-[(ethoxymethylene)amino]pyrrole (7) with 2-deoxy-2-fluoro-alpha-D-erythro-pentofuranosyl bromide (2) furnished an anomeric mixture of nucleosides (8a,b). This mixture was separated, and the individual anomers were treated with methanolic ammonia to effect a concomitant deblocking and ring closure. This furnished both anomers of 2'-deoxy-2'-fluoro-ara-toyocamycin (9a,b). The cyano moiety of 9b was converted to the carboxamide moiety to furnish 2'-deoxy-2'-fluoro-ara-sangivamycin (10) and to the thiocarboxamide moiety to furnish 2'-deoxy-2'-fluoro-ara-thiosangivamycin (11). The target compounds 10 and 11 showed similar antiproliferative activity against L1210 cells in vitro, with IC50's of 3 and 5 microM. Antiviral evaluation revealed a somewhat different pattern of activity. All analogs, both alpha and beta anomers, were active against human cytomegalovirus (HCMV), albeit the beta anomers were most active. The beta anomers also were active against herpes simplex virus type 1 (HSV-1) and human immunodeficiency virus (HIV). Compound 10 was most active in the series, ca. 10-fold more potent than 11; IC50's for 10 ranged from 4 to 25 nM for HCMV, HIV, and varicella zoster virus (VZV) and from 30 to 500 nM for HSV-1. Even though compound 10 was cytotoxic, which will probably preclude its use as an antiviral drug (IC50's = 0.2-5.5 microM), the difference between cytotoxicity and activity against HCMV, HIV, and VZV was sufficient to indicate specific activity against a viral target.

O R MANY YEARS, hip operations were regarded as extremely serious, not to say dangerous. Such operations were accompanied by a high rate of mortality, and on that account were rarely performed. In about the last ten years, however, hip surgery has been making constant progress. Today, new surgical techniques, especially insertion of inert matter (vitallium and acrylic) have made hip arthroplasty a frequent operation in departments of large hospitals which specialise in bone surgery. I n the Clinic for Orthopedic and Reconstructive Surgery of the Faculty of Medicine, University of Paris, directed by Professor Merle D'AubignC, in the last three years, I and my assistants have administered 395 anaesthetics in connection with major hip operations. These operations raise special problems in anaesthesia and transfusion. The object of this paper is to state these problems, to outline the methods evolved to deal with them, and to appreciate the results obtained.Among major hip operations, arthroplasty is now the most frequent. Perhaps it would be as well to mention here that in France two methods of arthroplasty are practised : Smith-Petersen's, based on the use of a vitallium cup: and Judet's, which involves substitution for the head of the femur, of a mushroom-shaped plastic prosthesis made of acrylic, the foot of which is introduced into the canal of the neck of the femur. I n addition, in cases of tumour or other pathological conditions requiring partial femorectomy, Merle d'AubignC has succeeded, within the last few years, in inserting large prostheses made of reinforced acrylic, replacing the head, neck and part of the shaft of the femur.W e do not consider as a major operation pinning fractures of the neck of the femur, which does not involve arthrotomy, or insertion of -TABLE 1 Arthroplasty with acrylic prosthesis 182 Cup arthroplasty 106 Arthrodesis 49 Resection of femur 14 Operation for fractured acetahulum 8 Others 36 Total 395 Extremes of age: 5 and 91 years. Above 60 years: 75. Average length of operation: 105 minutes. Extremes of length of operation: 40 and 270 minutes.-