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Three series of 2-arylidenebenzocycloalkanones 1-3 were prepared in order to compare the topography of the molecules with cytotoxicity. These compounds contain two aryl rings whose spatial relationships to each other were influenced by the size of the alicyclic ring and the nature of the substituents in the arylidene aryl rings. All compounds were evaluated against murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. From these results, 1l and 2c,l emerged as useful lead molecules and 1l was shown to significantly inhibit macromolecular DNA, RNA, and protein syntheses in L1210 cells. Various interatomic distances, bond angles, and a torsion angle of 19 representative compounds were determined by X-ray crystallography, and correlations between these data and the cytotoxicity were noted in nearly 40% of the cases examined. Structure-activity relationships revealed that in general, the steric properties of the groups in the arylidene aryl ring, as revealed by measurements of the molar refractivity values, contributed more to bioactivity than the electronic and hydrophobic properties of the aryl substituents. The compounds displayed little murine toxicity, which favors the decision to develop these molecules as cytotoxic and anticancer agents.
The previously developed method for the preparation of 2'-O-D-ribofuranosyl-nucleosides is extended to ribosylation of 2'-deoxynucleosides. The scope and limitations of this reaction are discussed.
Ever since the S-adenosylhomocysteine (AdoHcy, SAH) hydrolase was recognized as a pharmacological target for antiviral agents (J. A. Montgomery et al., J. Med. Chem. 25:626-629, 1982), an increasing number of adenosine, acyclic adenosine, and carbocyclic adenosine analogues have been described as potent SAH hydrolase inhibitors endowed with broad-spectrum antiviral activity. The antiviral activity spectrum of the SAH hydrolase inhibitors include pox-, rhabdo-, filo-, arena-, paramyxo-, reo-, and retroviruses. Among the most potent SAH hydrolase inhibitors and antiviral agents rank carbocyclic 3-deazaadenosine (C-c3 Ado), neplanocin A, 3-deazaneplanocin A, the 5'-nor derivatives of carbocyclic adenosine (C-Ado, aristeromycin), and the 2-halo (i.e., 2-fluoro) and 6'-R-alkyl (i.e., 6'-R-methyl) derivatives of neplanocin A. These compounds are particularly active against poxviruses (i.e., vaccinia virus), and rhabdoviruses (i.e., vesicular stomatitis virus). The in vivo efficacy of C-c3 Ado and 3-deazaneplanocin A has been established in mouse models for vaccinia virus, vesicular stomatitis virus, and Ebola virus. SAH hydrolase inhibitors such as C-c3Ado and 3-deazaneplanocin A should in thefirst place be considered for therapeutic (or prophylactic) use against poxvirus infections, including smallpox, and hemorrhagic fever virus infections such as Ebola.
No abstract is provided for this article.
The antiviral activity and interferon-inducing ability of single-, double-, and triple-stranded polynucleotides, modified at pyrimidine C-5 or purine N-7, were evaluated in primary rabbit kidney cells challenged with vesicular stomatitis virus. (1) There is a parallel increase in antiviral activity and the temperature at which double-stranded polynucleotides rearrange to inactive triple-stranded complexes. (2) When the purine N-7 of (A)(n) is replaced by CH, all resulting double-stranded complexes fail to provide antiviral protection or to induce interferon, even though such complexes meet all requirements previously recognized for interferon induction. (3) Competition experiments between inactive and active polynucleotides indicate that single-stranded polynucleotides apparently do not bind to the cellular receptor sites for interferon induction, whereas triple-stranded complexes and inactive double-stranded complexes bind to such receptor sites but, probably for conformational reasons, fail to trigger the necessary message for interferon induction.
Patients suffering from dendritic and geographic corneal ulcers or herpetic stromal keratitis were treated with topical BVDU [(E)-5-(2-bromovinyl)-2'-deoxyuridine, bromovinyldeoxyuridine] 0.1% eyedrops administered during the day only at 1-hour intervals. Treatment with other antiviral drugs, i.e., idoxuridine, trifluridine, vidarabine or Zovirax had failed to ameliorate the ocular disease in 102 patients when their treatment was switched to BVDU eyedrops. Under BVDU therapy, dendritic keratitis in 44 patients healed within an average 7.8 days. Similarly, geographic corneal ulcers in 26 patients and stromal keratitis in 32 patients healed within an average period of 11.2 days and 30.7 days, respectively. Associated therapy with topical corticosteroids was stopped in 65 patients when the antiviral treatment was switched. However, topical corticosteroids had to be used together with BVDU drops to arrest stromal inflammation in 49 patients. Ultimately, 36 patients became corticosteroid-dependent. Except for local hypersensitivity reaction in three patients, BVDU eyedrops did not cause any toxic side effects.
The pig liver esterase (PLE) assay has been designed to "reproduce" in vitro the first step of the metabolism of phosphoramidate pro-drugs that generates the free amino acyl phosphoramidate intermediate which has been described as a key metabolite necessary but not sufficient for the biological activity. The method could be used as a predictive tool for the likely in vitro biological activity as well as for Structure-Activity Relationship establishment (SAR).
