PubMed · 8607478
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M N Abelson. 1996. Database or spreadsheet--what's the difference.. https://doi.org/10.1016/s0889-5406(96)70156-7
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Inhibitors of HIV integrase are currently being sought as potential new therapeutics for the treatment of AIDS. A large number of inhibitors discovered to date contain the o-bis-hydroxy catechol structure. In an effort to discover structural leads for the development of new HIV integrase inhibitors which do not rely on this potentially cytotoxic catechol substructure, NSC 310217 was identified using a three-point pharmacophore search based on its assigned structure N-(2-hydroxybenzoyl)-N-(2-hydroxy-3-phenoxypropyl)hydrazine (1). When a sample of NSC 310217 was obtained from the NCI repository, it was shown to exhibit potent inhibition of HIV-1 integrase (3'-processing IC50 = 0.6 microgram/mL). In work reported herein, we demonstrate that NSC 310217, rather than containing 1, which has no inhibitory potency against HIV-1 integrase, is comprised of roughly a 1:1 mixture of N-(2-hydroxybenzoyl)-N'-(2-hydroxy-3-phenoxypropyl)hydrazine (6) and N,N'-bis-salicylhydrazine 7, with all inhibitory potency residing with compound 7(IC50 = 0.7 microM for strand transfer). In subsequent structure-activity studies on 7, it is shown that removing a single amide carbonyl (compound 14, IC50 = 5.2 microM) or replacing one aromatic ring system with a naphthyl ring (compound 19, IC50 = 1.1 microM) can be accomplished with little loss of inhibitory potency. Additionally, replacing a single hydroxyl with a sulfhydryl (compound 23, IC50 = 5.8 microM) results in only moderate loss of potency. All other modifications examined, including the replacement of a single hydroxyl with an amino group (compound 22), resulted in complete loss of potency. Being potent, structurally simple, and non-catechol-containing, compounds such as 7 and 14 may provide useful leads for the development of a new class of HIV integrase inhibitor.
Clinical and biochemical data were collected prospectively from 8032 jaundiced patients to form a database as part of a EU-supported project on computer-aided diagnosis. Patients were recruited prospectively from centres in all EU-countries and some other countries as well. Five hundred and twenty-eight jaundiced patients were collected from four centres in Denmark. Alcoholic cirrhosis, acute alcoholic liver disease and malignancy of the pancreas or the biliary tract were more common in the Danish data base: 49% of cases in Denmark as compared to 30% of cases in the international database. Viral hepatitis was underrepresented in Denmark, 16% as compared to 23% in the international group. A crude Bayesian diagnostic programme on the total database with 17 diagnostic groups achieved 63% accuracy. For the 528 Danish cases the diagnostic accuracy was 64% when the European data base was used, whereas it increased to 81% when only the Danish data base was taken as basis for the calculations. In conclusion, we found a drop in diagnostic accuracy for the Danish patients when using the large European data base instead of the national one.