Antitumor and antiviral activity of synthetic alpha- and beta-ribonucleosides of certain substituted pyrimido[5,4-d]pyrimidines: a new synthetic strategy for exocyclic aminonucleosides

A novel and direct synthesis of the antiviral and antitumor agent 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine (ARPP, 8) and its alpha-anomer (11) has been developed. Treatment of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (1) with 2,3-O-isopropylidene-D-ribofuranosylamine gave an anomeric mixture of 2,4,6-trichloro-8-(2,3-O-isopropylidene-beta- and -alpha-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidines (3 and 4) in a ratio of 1.0:0.7. A nucleophilic displacement of the 4-chloro group of 3 and 4 with NH3 furnished 4-amino-2,6-dichloro-8-[(2,3-O-isopropylidene-beta-D-ribofuranosyl)amino ] pyrimido[5,4-d]pyrimidine (6) and its alpha-anomer (9), respectively. Catalytic hydrogenation of 6 and 9, followed by deisopropylidenation gave ARPP (8) and the alpha-anomer 11, respectively. Similarly, 3 and 4 have been transformed to 4-methoxy-8-(beta-D-ribofuranosylamino)pyrimido-[5,4-d]pyrimidine (MRPP, 14) and its alpha-anomer (17). Application of this procedure to 3 with NH2Me or NHMe2 resulted in the synthesis of 4-(methylamino)- and 4-(dimethylamino)-8-(beta-D-ribofuranosylamino)pyrimido [5,4-d]pyrimidine (24 and 27, respectively). A synthesis of 8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidin-4(3H)-one (21) has also been accomplished from 3 in three steps. Selective hydrogenation of 6 furnished 4-amino-6-chloro-8-[(2,3-O-isopropylidene-beta-D-ribofuranosyl)amino] pyrimido[5,4-d]pyrimidine (36), the structure of which was established by single-crystal X-ray diffraction analysis. Deisopropylidenation of 36 gave 6-chloro-ARPP (37). Extended treatment of 36 with NH3 furnished 4,6-diamino-8-[(2,3-O-isopropylidene-beta-D-ribofuranosyl)amino]pyrimido [5,4-d]pyrimidine (34), which on deisopropylidenation gave 6-amino-ARPP (35). An unambiguous synthesis of 34 and 36 has also been accomplished by the reaction of 4,6,8-trichloropyrimido[5,4-d]pyrimidine (28) with 2, followed by the treatment with NH3. Nucleophilic displacement studies with 1, 6, and 28 indicated the reactivity of the halogens in these compounds is in the order of 8 greater than 4 greater than 6 greater than 2. The structures of 3 and 9 have been assigned on the basis of 1H NMR data and further confirmed by single-crystal X-ray diffraction analysis. The exocyclic aminonucleosides synthesized during this study were tested for their activity against several RNA and DNA viruses in vitro and against L1210, WI-L2, and LoVo/L in cell culture. The effect of these compounds on the de novo nucleic acid biosynthesis has been studied. Compound 14 (MRPP) exhibited enhanced activity against L1210 in vivo, when compared to ARPP (8).     

Metarrhizium anisopliae as a Cause of Sinusitis in Immunocompetent Hosts

Metarrhizium anisopliae is a common pathogen of insects and has even been used to control insect populations. It is rarely isolated from human or animal sources, but recently, there have been three reported cases of disease, two in humans and one in a cat. We present our experience with five isolates from human sources, including two that were the apparent causes of two cases of sinusitis in immunocompetent hosts. The first patient was a 36-year-old male with frontal and ethmoid sinusitis, and the second was a 79-year-old female with chronic sinusitis. Both patients underwent surgery, and pathology of the surgical specimens revealed branching hyphae. Cultures grew only Metarrhizium species. Neither patient received antifungal therapy, and both did well postoperatively. The other three isolates were cultured from bronchoalveolar lavage specimens but were not felt to be clinically significant. Antifungal susceptibility testing using the National Committee for Clinical Laboratory Standards macrobroth method revealed that all isolates were resistant to amphotericin B, 5-flucytosine, and fluconazole. Itraconazole and newer azole compounds were more active. Metarrhizium species may cause disease in humans, even those without evidence of immunosuppression, and are apparently highly resistant to amphotericin B in vitro.     

Leprosy survey in industries in Bombay

Population surveys for leprosy in industrial cities like Bombay revealed that about 60% of adult subjects especially males could be examined. The fact that the prevalence rate of leprosy particularly multibacillary type is much higher in this segment of population as compared to other groups indicates the importance of examining this population at their workspot like industries. 22287 industrial workers were examined for leprosy by paramedical auxiliaries in their establishments and 270 leprosy cases were detected (P.R. 12/1000). However, only 13 multibacillary cases (P.R. 0.5/1000) could be unearthed. 12 patients were with grade II and above. 184 (83%) were untreated. 161 (60%) patients reported for treatment. With available resources, case holding of patients who are not within the control area of the project becomes a challenging job for paramedical workers though large number of leprosy cases are detected amongst industrial workers. If industrial management arranges treatment for leprosy patients without dislocating them from their service, the pool of infection in the urban community will be reduced and can contribute tremendously towards urban leprosy control programme.     

Inhibition of experimental deoxyribonucleic acid virus-induced encephalitis by 9-beta-D-arabinofuranosylhypoxanthine 5'-monophosphate.

9-beta-d-Arabinofuranosylhypoxanthine 5'-monophosphate (ara-HxMP) significantly controlled the development of encephalitis produced by deoxyribonucleic acid viruses in mice. In most experiments the activities of ara-HxMP and 9-beta-d-arabinofuranosyladenine (ara-A) were determined simultaneously. In the intracerebral (target organ) and intravenous therapy experiments, ara-HxMP had a pronounced advantage over ara-A since the water solubility of ara-HxMP enabled it to be used in much higher concentrations. In experiments where the two drugs were administered intraperitoneally or orally they exhibited similar activity. In several intraperitoneal therapy experiments ara-HxMP was tested alone, using various treatment schedules and dosages. In these experiments, efficacy was observed in groups that had treatments initiated as late as 72 h after virus inoculation.     

Vancomycin-resistant enterococcal meningitis treated with intrathecal streptomycin

Enterococcal meningitis is a rare complication of neurosurgical procedures. We present a patient who developed vancomycin-resistant enterococcal ventriculitis - meningitis after a brain tumor resection and ventriculoperitoneal shunt placement, treated successfully with intrathecal streptomycin through bilateral cerebrospinal fluid drainage catheters in addition to systemic antibiotics. This is the first report of such treatment for this resistant organism.     

Cladophialophora bantiana brain abscess in an immunocompetent patient

Cladophialophora bantiana is a dematiaceous mold with a predilection for causing central nervous system infection, particularly in normal hosts. A case involving a 79-year-old immunocompetent woman who presented with left-sided weakness and a ring-enhancing brain lesion is reported. She underwent surgical excision, which revealed a brain abscess due to C bantiana. The patient was treated with liposomal amphotericin B for several weeks, then switched to voriconazole and flucytosine, but eventually succumbed to the infection. Therapy is not standardized for this rare mycosis, and mortality remains high, even in immunocompetent patients. Additional studies to understand the pathogenesis of this infection and to improve outcomes are needed.     

Activity of purine analogs against Leishmania tropica within human macrophages in vitro

The activity of purine analogs against Leishmania tropica in human monocyte-derived macrophages in vitro was determined. Formycin B, formycin A, formycin B and A monophosphate, and formycin A triphosphate all had 50% effective doses of 0.02 to 0.04 microM and eliminated 90% of organisms at less than or equal to 0.5 microM. Allopurinol ribonucleoside was much less active: the 50% effective dose was 76 to 190 microM, and 90% of organisms were not eliminated at the highest dose tested (190 microM). 7-Deazainosine had a low 50% effective dose (0.2 microM), but only 80% of organisms were eliminated at 4 microM. Thio derivatives were as active as or less active than the parent compounds. These data suggest that certain inosine analogs are much more active than others against macrophage-contained Leishmania spp. such as are found in human lesions. However, because toxicity to the human macrophage hosts generally paralleled antileishmanial activity, the more active compounds might also be more toxic to human cells. The activity of 3-deazaguanosine (50% effective dose, 3.6 microM) in this model suggests that guanosine derivatives may have potential as antileishmanial agents.     

Dematiaceous fungi

Dematiaceous fungi are the etiologic agents of phaeohyphomycosis and are increasingly recognized as causing disease in humans. A wide variety of infectious syndromes are seen, from local infections due to trauma to widely disseminated infection in immunocompromised patients. Pulmonary disease may be divided into allergic bronchopulmonary and nonallergic syndromes, depending on the species. These fungi have unique pathogenic mechanisms owing to the presence of melanin in their cell walls, which imparts the characteristic dark color to their spores and hyphae. Melanin is a known virulence factor in certain fungi, including Cryptococcus neoformans and Wangiella dermatitidis. Therapy depends upon the clinical syndrome. Local infection may be cured with excision alone, whereas systemic disease is often refractory to therapy. Azoles such as itraconazole and voriconazole have the most consistent in vitro activity, though there is more clinical experience with itraconazole. Further studies are needed to better understand the pathogenesis and treatment of these uncommon infections.