The E2 protein is required for the replication of human papillomaviruses (HPVs), which are responsible for anogenital warts and cervical carcinomas. Using an NMR-based screen, we tested compounds for binding to the DNA-binding domain of the HPV-E2 protein. Three classes of compounds were identified which bound to two distinct sites on the protein. Biphenyl and biphenyl ether compounds containing a carboxylic acid bind to a site near the DNA recognition helix and inhibit the binding of E2 to DNA. Benzophenone-containing compounds which lack a carboxylic acid group bind to the beta-barrel formed by the dimer interface and exhibit negligible effects on the binding of E2 to DNA. Structure-activity relationships from the biphenyl and biphenyl ether compounds were combined to produce a compound [5-(3'-(3",5"-dichlorophenoxy)-phenyl)-2,4-pentadienoic acid] with an IC50 value of approximately 10 microM. This compound represents a useful lead for the development of antiviral agents that interfere with HPV replication and further illustrates the usefulness of the SAR by NMR method in the drug discovery process.

The material in this chapter is divided into three sections. The first section is intended to provide a general overview of the physical/chemical properties common to all epidithiodioxopiperazines. The second section introduces the structures of naturally occurring epipolythiodioxopiperazines and related metabolites which have been characterized. Lastly, the third section is devoted to a discussion of the more interesting • biosyntheses of several of the metabolites. Physical/chemical Properties of epipolythiodioxopiperazinesThe epipolythiodioxopiperazine ring system possesses a variety of physical properties which ultimately control the chemical reactivity of this unusual ring system. The disulfide bridge is highly strained and is easily reduced with mild reducing agents such as sodium borohydride. The strain inherent in the disulfides is a direct consequence of the small CSSC dihedral angles found in the epidithiodioxopiperazines compared to CSSC dihedral angles found in acyclic disulfides. Normal dihedral angles of 7 4-105° are often observed in acyclic disulfides, 4 whereas the CSSC dihedral angles present in the epidithiodioxopiperazines range from 8-18°.2d Analysis of X-ray structures indicate the S-S bonds in the epidithiodioxopiperazines are longer (2.059 vs 2.03-2.05 A) than in acyclic disulfides. 2d Analysis of the X-ray structures of the epidithiodioxopiperazines also indicates the Blsdethio-(dlmethylthio)acetylaranotln (LL-S88~)

The core bicyclo[7.3.0]enediyne 3 has been synthesized from the protected cyclohexane-1,2-dione 6 and enediyne component 9. Conversion of 20 into more highly functionalized enediynes was accomplished by oxidation and amination to give 27. Protection of 27, and conversion into 31, gave on treatment with (MeO)2P(O)CH2CO2Me the lactone 32, which was transformed into the trisulfide 39. All attempts to deprotect 39, using conditions that other workers successfully applied to similar substrates, only resulted in the cyclic sulfides 42 and 43.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.