Mohamed Nasr

Anthraquinones as a new class of antiviral agents against human immunodeficiency virus

Various anthraquinones substituted with hydroxyl, amino, halogen, carboxylic acid, substituted aromatic group, and sulfonate were tested to determine their activity against human immunodeficiency virus type 1 (HIV-1) in primary human lymphocytes. Among the compounds tested, polyphenolic and/or polysulfonate substituted anthraquinones were found to possess the most potent antiviral activity. Hypericin, an anthraquinone dimer previously shown to have activity against nonhuman retroviruses also exhibited anti-HIV-1 activity in lymphocytes. the active anthraquinones inhibited HIV-1 reverse transcriptase. However, this enzyme inhibition was selective only for 1,2,5,8-tetrahydroanthraquinone and hypericin. Hypericin interacts nonspecifically with protein suggesting that this effect may dictate its inhibitory activity against the viral reverse transcriptase.

Antimicrosporidial Activities of Fumagillin, TNP-470, Ovalicin, and Ovalicin Derivatives In Vitro and In Vivo

ABSTRACT Therapies for microsporidiosis in humans are limited, and fumagillin, which appears to be the most broadly effective antimicrosporidial drug, is considered to be moderately toxic. The purpose of this study was to apply an in vitro drug screening assay for Encephalitozoon intestinalis and Vittaforma corneae and an in vivo athymic mouse model of V. corneae infection to assess the efficacy of TNP-470 (a semisynthetic analogue of fumagillin), ovalicin, and eight ovalicin derivatives. TNP-470, ovalicin, and three of the ovalicin derivatives inhibited both E. intestinalis and V. corneae replication by more than 70% in vitro. Another three of the ovalicin derivatives inhibited one of the two microsporidian species by more than 70%. None of the treated athymic mice survived the V. corneae infection, but they did survive statistically significantly longer than the untreated controls after daily treatment with fumagillin administered at 5, 10, and 20 mg/kg of body weight subcutaneously (s.c.), TNP-470 administered at 20 mg/kg intraperitoneally (i.p.), or ovalicin administered at 5 mg/kg s.c. Of two ovalicin derivatives that were assessed in vivo, NSC 9665 given at 10 mg/kg i.p. daily also statistically significantly prolonged survival of the mice. No lesions associated with drug toxicity were observed in the kidneys or livers of uninfected mice treated with these drugs at the highest dose of 20 mg/kg daily. These results thus support continued studies to identify more effective fumagillin-related drugs for treating microsporidiosis.

Computer Assisted Structure-Antileukemic Activity Correlations of Organotin Compounds and Initial Exploration of their Potential Anti-HIV Activity

The National Cancer Institute (NCI) and others have a continuing interest in exploring the anticancer and recently the anti-HIV potential of metal and metalloid compounds (Cleare et al 1980; Lippard 1983; Crowe et al 1980). The number of metal-containing compounds in the NCI collection is given in Table 1. Organotin compounds are the largest class among metals as represented by more than 2,000 compounds. This emphasis is the natural consequence of the wide biological use (Cardarelli 1972; Arakawa et al 1988) of tin compounds and their subsequent availability for screening by the NCI. A good deal of work has been done on the chemistry (Davis et al 1980; Wardell 1967), toxicology (Cardarelli 1986; Smith et al 1975), and metabolism (Thayer 1974; Kimmel 1977) of tin compounds. This study focuses on the structure-anticancer activity of tin-containing compounds evaluated by the NCI.

Structure-Activity Correlations of Natural Products with Anti-HIV Activity

The search for safe and effective therapies to treat infections caused by the human immunodeficiency virus (HIV) and related opportunistic infections (OI’s) are among the highest priorities of the National Institutes of Health. The Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID) supports rational drug design and targeted drug discovery for HIV and the OI’s through investigator-initiated research grants including the National Cooperative Drug Discovery Group programs.

Structure-Activity Correlations of 2′,3′-Dideoxy- and 2′,3′-Didehydro-2′,3′-Dideoxypyrimidine Nucleosides as Potential Anti-HIV Drugs

The first compound approved for the clinical treatment of human immunodeficiency virus (HIV) was the nucleoside analog 3′-azido-3′-deoxythymidine (AZT; zidovudine).1 Discovery of its antiviral activity prompted extensive evaluation of other nucleosides for anti-HIV efficacy and to date 2′,3′-dideoxyinosine (ddl; didanosine) and 2′,3′-dideoxy-cytidine (ddC; zalcitabine) additionally have been approved on a limited basis for clinical treatment of this virus. These nucleosides share a common mode of action, namely phosphorylation to the corresponding 5′-triphosphates which act as inhibitors of the virus-encoded reverse transcriptase.2.3 Substantial effort also has been directed towards developing non-nucleoside drugs (e.g. protease inhibitors, tat antagonists) which inhibit viral targets other than reverse transcriptase.4 The pursuit of more effective nucleoside analogs nonetheless remains an area of high interest to many investigators. This review provides detailed structure-activity data for two classes of nucleosides, the 2′,3′-dideoxy-and 2′,3′-didehydro-2′,3′-dideoxypyrimidine nucleosides, in the hopes it will prove useful to investigators in identifying new synthetic target molecules while avoiding unnecessary duplication of previous synthetic efforts.

Computer-assisted structure — Antileukemic activity analysis of purines and their aza and deaza analogs

The National Cancer Institute (NCI), in a continuing effort to discover novel anticancer leads, has screened more than 350,000 compounds. Thus, extensive chemical and biological database files have become available. The recent establishment of the chemistry-biology computer interlink offers the opportunity to undertake carefully planned structure-activity studies. Although a selective acquisition approach in the screening program is now adopted by the NCI [1] promising antitumor leads still have to be developed from the screening of large numbers of compounds in various tumor systems. These novel leads can then be optimized through both structure-activity analysis of the total NCI file and analog synthesis.

Structure‐Activity Correlations of Pyrimidine and Purine Dideoxynucleosides as Potential Anti‐HIV Drugs

The Developmental Therapeutics Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), has established a computerized database with the capacity to analyze the structure-activity relationships for active and inactive anti-HIV compounds. The following are the results of analysis of data accumulated so far on in vitro anti-HIV testing of more than 350 dideoxynucleosides (ddN) and analogues. Compounds that have shown promising activity against HIV are 2’,3’-dideoxypyrimidine &d purine nucleosides’ (TABLES 1-3) and t o a lesser extent acyclonucleoside analogues2 (FIGURES 1 and 2). Only 3’or 2’azido (TABLE 4) or -fluoro (TABLE 5) substitution has shown anti-HIV activity. 3’-Azido or 3‘-fluoro enhanced the activity of the dideoxypyrimidine nucleosides’ but not dideoxypurine nucleosides. Unsubstituted sugar is optimal for activity of purine ddNs. 3’-Substitution with amino, alkyl, cyano, alkoxy, thioalkyl, thiocyanato (SCN), isothiocyanato (NCS), and 3’-hdo other than fluorine gave inactive compounds. 3’-Acetylenic groups or pseudohalogens have not been reported in the literature. Introduction of a 2’-ara-fluoro substituent retained the activity of the purine ddN and to a lesser extent the pyrimidine ddN, whereas 2’-erythro fluoro inactivated both purine and pyrimidine ddN. Threo 3’-fluoro gave inactive compounds, whereas erythro 3’-fluOrO gave active compounds, particularly with pyrimidine ddN. Introduction of a 2’-OH in 3’-azidopyrimidine ddN abolished activity. A 2’,3’-double-bond inactivated purine, but not pyrimidine, ddN (TABLE 6). No ddN with 3’,4‘, or 1’,2’-3’,4‘ double bonds have been reported. 5-Halogen-substituted pyrimidine ddN are active4 (TABLE 7). This was attributed to the larger size of C1, Br, and I but not F, which may approach the size of a methyl group, so increasing the affinity of these compounds to thymidine kinase. Only one isocytidine ddN has been reported and has anti-HIV activity. Monomethylation of the 6-amino group in ddA or the 4-amino group in ddC may have enhanced the activity of these compounds, whereas introduction of ethyl, two methyl groups, or benzyl abolished the activity. Carbocyclic purine ddN but not pyrimidine analogues have anti-HIV activity.