A series of over 70 difluoropurine analogs was synthesized by varying the C-2, 6 and 8 substituents about the purine ring system. After initial in vitro and in vivo screening, testing concentrated on the 2,6-diaminopurine analog (dFdAP) and the guanosine analog (dFdG). dFDAP appears to be a prodrug for dFdG. Both compounds significantly inhibited mammary tumor growth in mice, caused a moderate inhibition in ovarian and lymphosarcoma models, and demonstrated no activity in lung and melanoma models. This is a narrower spectrum of activity than that of gemcitabine (dFdC). The antitumor activity of dFdAP in human xenografts that are refractory to standard clinical agents was comparable or superior to that of gemcitabine. However, during the preliminary toxicology testing, dFdG was associated with several deaths caused by cardiac toxicity. Therefore, although dFdG is a potentially useful oncolytic, further investigation is required.

To identify the minimal structural elements necessary for biological activity, the rigid tricyclic nucleus of the known human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor tetrahydroimidazobenzodiazepinthione was subjected to systematic bond disconnection to obtain simpler structures. A rational selection and testing of modeled analogs containing these potential pharmacophoric moieties led to the discovery of a new series of nonnucleoside inhibitors of RT. The lead compound of this new PETT series of nonnucleoside RT inhibitors, N-(2-phenylethyl)-N'-(2-thiazolyl)thiourea (LY73497), was found to inhibit HIV-1 but not HIV-2 or simian immunodeficiency virus in cell culture at micromolar concentrations. This derivative was also found to inhibit HIV-1 RT. Through an integrated effort involving synthesis and molecular modeling, compounds with nanomolar potency against HIV-1 in cell culture were developed. In these studies, LY300046-HCl was identified as a potent nonnucleoside inhibitor of HIV-1 RT possessing favorable pharmacokinetic properties.

Phenylethylthiazolylthiourea (PETT) derivatives have been identified as a new series of non-nucleoside inhibitors of HIV-1 RT. Structure-activity relationship studies of this class of compounds resulted in the identification of N-[2-(2-pyridyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea hydrochloride (trovirdine; LY300046.HCl) as a highly potent anti-HIV-1 agent. Trovirdine is currently in phase one clinical trials for potential use in the treatment of AIDS. Extension of these structure-activity relationship studies to identify additional compounds in this series with improved properties is ongoing. A part of this work is described here. Replacement of the two aromatic moieties of the PETT compounds by various substituted or unsubstituted heteroaromatic rings was investigated. In addition, the effects of multiple substitution in the phenyl ring were also studied. The antiviral activities were determined on wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses derived thereof, Ile100 and Cys181, in cell culture assays. Some selected compounds were determined on double-mutant viruses, HIV-1 (Ile 100/Asn103) and HIV-1 (Ile100/Cys181). A number of highly potent analogs were synthesized. These compounds displayed IC50's against wild-type RT between 0.6 and 5 nM. In cell culture, these agents inhibited wild-type HIV-1 with ED50's between 1 and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant HIV-1 RT (Ile 100) with IC50's between 20 and 50 nM and mutant HIV-1 RT (Cys 181) with IC50's between 4 and 10 nM, and in cell culture they inhibited mutant HIV-1 (Ile100) with ED50's between 9 and 100 nM and mutant HIV-1 (Cys181) with ED50's between 3 and 20 nM.

A new method for the synthesis of chiral azetidinones bearing a carbon-carbon bond at the 4-position is described. The preparation involves a stereoselective alkylation-reduction of a silylated 4-phenylsulfonyl azetidinone. The utility of this method was demonstrated by a formal total synthesis of loracarbef.

The synthesis and biological evaluation of novel 1-carba-1-dethiacephalosporins exhibiting activity against anaerobic pathogens are described. The nitrothiazole substituent was determined to be crucial to maintaining this activity. The pharmacokinetic parameters and initial toxicological profile of the lead compound are discussed.

The synthesis and antimicrobial activity of several new 1-carba-1-dethiacephalosporins is described. The discovery of unique activity of some of the analogues against methicillin-resistant Staphylococcus aureus led to the development of a structure-activity relationship designed to optimize this activity. The results of this investigation along with the pharmacokinetic characteristics of select compounds are described.

The synthesis of 1-carba-1-dethiacephalosporin nuclei is described. The new route utilizes a readily-available penicillin derivative as starting material and features an intramolecular ring closure to form the six-membered ring.

AbstractChemInform 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.

AbstractChemInform 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.

ChemInformVolume 21, Issue 49 Natural Products ChemInform Abstract: Comparative Reactivity of 1-Carba-1-dethiacephalosporins with Cephalosporins. L. C. BLASZCZAK, L. C. BLASZCZAK Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorR. F. BROWN, R. F. BROWN Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorG. K. COOK, G. K. COOK Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorW. J. HORNBACK, W. J. HORNBACK Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorR. C. HOYING, R. C. HOYING Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorJ. M. INDELICATO, J. M. INDELICATO Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorC. L. JORDAN, C. L. JORDAN Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorA. S. KATNER, A. S. KATNER Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorM. D. KINNICK, M. D. KINNICK Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorJ. H. III MCDONALD, J. H. III MCDONALD Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorJ. M. JUN. MORIN, J. M. JUN. MORIN Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorJ. E. MUNROE, J. E. MUNROE Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorC. E. PASINI, C. E. PASINI Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this author L. C. BLASZCZAK, L. C. BLASZCZAK Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorR. F. BROWN, R. F. BROWN Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorG. K. COOK, G. K. COOK Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorW. J. HORNBACK, W. J. HORNBACK Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorR. C. HOYING, R. C. HOYING Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorJ. M. INDELICATO, J. M. INDELICATO Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorC. L. JORDAN, C. L. JORDAN Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorA. S. KATNER, A. S. KATNER Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorM. D. KINNICK, M. D. KINNICK Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorJ. H. III MCDONALD, J. H. III MCDONALD Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorJ. M. JUN. MORIN, J. M. JUN. MORIN Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorJ. E. MUNROE, J. E. MUNROE Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this authorC. E. PASINI, C. E. PASINI Lilly Res. Lab., Eli Lilly Co., Lilly Corp. Center, Indianapolis, IN 46285, USASearch for more papers by this author First published: December 4, 1990 https://doi.org/10.1002/chin.199049315AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume21, Issue49December 4, 1990 RelatedInformation

Nine matched pairs of cephalosporins and their 1-carba-1-dethiacephalosporin analogues have been compared with regard to microbiological activity, beta-lactam carbonyl infrared absorption, and aqueous stability. In general the microbiological activity of the pairs of compounds were very similar across a broad range of bacteria. The infrared absorption bands for the beta-lactam carbonyls of the pairs indicated a general trend for the 1-carba-1-dethiacephalosporins to absorb at lower frequencies than the corresponding cephalosporins. All of the 1-carba-1-dethiacephalosporins did however present a striking stability enhancement over their cephalosporin counterparts at pH = 10 or 11 in water. This marked contrast of MIC similarity with the observed differences in chemical reactivity clearly demonstrates hydroxide ion catalyzed hydrolysis is not a good model for transpeptidase activity unless the compounds comprise a limited domain of structural type.