Ophiobolin M and analogues, noncompetitive inhibitors of ivermectin binding with nematocidal activity
Athanasios TsipourasA. AdefaratiJan S. TkaczEaster G. FrazierSusan P. RohrerElizabeth T. BirzinAvery RosegayDeborah L. ZinkMichael GoetzSheo B. SinghJames M. Schaeffer
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis and Biological Evaluation of C-3'-Modified Analogs of 9(R)-DihydrotaxolLeping Li, Sheela A. Thomas, Larry L. Klein, Clinton M. Yeung, Clarence J. Maring, David J. Grampovnik, Paul A. Lartey, and Jacob J. PlattnerCite this: J. Med. Chem. 1994, 37, 17, 2655–2663Publication Date (Print):August 19, 1994Publication History Published online1 May 2002Published inissue 19 August 1994https://pubs.acs.org/doi/10.1021/jm00043a005https://doi.org/10.1021/jm00043a005research-articleACS PublicationsRequest reuse permissionsArticle Views280Altmetric-Citations28LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
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As a continuation of our structure−activity relationship study of substituted 2-phenyl-4-quinolones and flavonoids as antitumor and antiviral agents, a series of 5,6,7,8-substituted-2-phenylthiochromen-4-ones has been synthesized by condensation of substituted thiophenols and ethyl benzoylacetates. Target compounds were evaluated for biological activity. Among them, compounds 7, 10, 12, and 13 displayed significant growth inhibitory action against a panel of tumor cell lines including human ileocecal carcinoma (HCT-8), murine leukemia (P-388), human melanoma (RPMI), and human central nervous system tumor (TE671) cells. Compounds 10, 12, and 19 displayed DNA topoisomerase I inhibitory activity in vitro and compound 11 was an in vitro, inhibitor of DNA topoisomerase II. Compound 11 was most active (ED50 value, 0.65 μM) against HIV in acutely infected H9 lymphocytes and had a therapeutic index of about 5.
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Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar K(i) values, approximately 10-20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryostatins.
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The Δ7,8 olefinic linkages within (+)-calanolide A (1) and (−)-calanolide B (2) were catalytically reduced to determine impact on the anti-HIV activity of the parent compounds. In addition, a series of structure modifications of the C-12 hydroxyl group in (−)-calanolide B was made to investigate the importance of that substituent to the HIV-1 inhibitory activity of these coumarins. A total of 14 analogs were isolated or prepared and compared to (+)-calanolide A and (−)-calanolide B in the NCI primary anti-HIV assay. While none of the compounds showed activity superior to the two unmodified leads, some structure−activity requirements were apparent from the relative anti-HIV potencies of the various analogs.
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Very little is known about the structure-activity relationship of quinolone antibacterials at the 2-position. Because of the loss of biological activity with 2-methyl and 2-hydroxyl substitution, modifications at C-2 were generally considered to be unfavourable. Quinolone derivatives having a ring between positions 1 and 2 were recently shown to have biological activity. The sulfur-bridged analogs such as the benzothiazolo[3,2-a]quinolone, KB-5246 and NAD-394 have been reported to be highly active in vitro. The authors have synthesized 2-methylthiociprofloxacin, 2-methylofloxacin, the 5-oxopyrrolo[1,2-a]quinoline and isothiazolonaphthyridine to assess the importance of the sulfur atom on biological activity as well as the effect of C-2 substituent on the spatial arrangements of N-1 or the 3-carboxylic group. It was found that the planarity between the 4-keto and 3-carboxylic acid groups of quinoline molecules is the most important criterion for biological activity. The syntheses of the above four compounds are also described.
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis and biological activity of 5-amino- and 5-hydroxyquinolones, and the overwhelming influence of the remote N1-substituent in determining the structure-activity relationshipJohn M. Domagala, Alex J. Bridges, Townley P. Culbertson, Laura Gambino, Susan E. Hagen, Gregory Karrick, Kenneth Porter, Joseph P. Sanchez, Josephine A. Sesnie, and Cite this: J. Med. Chem. 1991, 34, 3, 1142–1154Publication Date (Print):March 1, 1991Publication History Published online1 May 2002Published inissue 1 March 1991https://pubs.acs.org/doi/10.1021/jm00107a039https://doi.org/10.1021/jm00107a039research-articleACS PublicationsRequest reuse permissionsArticle Views918Altmetric-Citations45LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
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