A New Strategy To Improve the Metabolic Stability of Lactone: Discovery of (20<i>S</i>,21<i>S</i>)-21-Fluorocamptothecins as Novel, Hydrolytically Stable Topoisomerase I Inhibitors

Miao, Zhenyuan; Zhu, Lingjian; Dong, Guoqiang; Zhuang, Chunlin; Wu, Yang‐Chang; Wang, Shengzheng; Guo, Zhenhong; Liu, Yang; Wu, Shanchao; Zhu, Shiping; Fang, Kun; Yao, Jing; Li, Jian; Sheng, Chunquan; Zhang, Wannian

doi:10.1021/jm400906z

Cited by 39 publications

(23 citation statements)

References 43 publications

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“…114 The lactone moiety of the quinoline-based alkaloid camptothecin (242), considered to be critical for antitumor activity, is subject to hydrolytic ring opening under physiological conditions which limits its therapeutic utility. 115 Replacing the lactone CO …”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Applications of Fluorine in Medicinal Chemistry

et al. 2015

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The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Applications of Fluorine in Medicinal Chemistry

et al. 2015

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“…) exhibited the best antiproliferative activity against all three tested cancer‐cell lines (IC 50 range: 0.71−0.07 μM), which was twofold (A549) and sixfold (HCT116) more active than CPT. This compound represents a promising lead for further optimization …”

Section: Biological Activity Of Cpt and Related Derivativesmentioning

confidence: 99%

“…This compound represents a promising lead for further optimization. 81 In continuing these efforts, our group recently reported that a series of 20-sulfonylamidine CPT derivatives displayed potent antitumor activity with drug-resistance profiles significantly different from those of CPT. Among them, compound 166 ( Fig.…”

Section: A B and E Ring Modified Cpt Analogsmentioning

confidence: 99%

Perspectives on Biologically Active Camptothecin Derivatives

et al. 2015

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Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.

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“…Wells containing no drugs were used as blanks. Concentration of the compounds that inhibited cell growth by 50% ( IC 50 ) was calculated [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Sulfamide and Triazole Benzodiazepines as Novel p53-MDM2 Inhibitors

Zhuang

et al. 2014

IJMS

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A series of sulfamide and triazole benzodiazepines were obtained with the principle of bioisosterism. The p53-murine double minute 2 (MDM2) inhibitory activity and in vitro antitumor activity were evaluated. Most of the novel benzodiazepines exhibited moderate protein binding inhibitory activity. Particularly, triazole benzodiazepines showed good inhibitory activity and antitumor potency. Compound 16 had promising antitumor activity against the U-2 OS human osteosarcoma cell line with an IC50 value of 4.17 μM, which was much better than that of nutlin-3. The molecular docking model also successfully predicted that this class of compounds mimicked the three critical residues of p53 binding to MDM2.

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A New Strategy To Improve the Metabolic Stability of Lactone: Discovery of (20S,21S)-21-Fluorocamptothecins as Novel, Hydrolytically Stable Topoisomerase I Inhibitors

Cited by 39 publications

References 43 publications

Applications of Fluorine in Medicinal Chemistry

Applications of Fluorine in Medicinal Chemistry

Perspectives on Biologically Active Camptothecin Derivatives

Design, Synthesis and Biological Evaluation of Sulfamide and Triazole Benzodiazepines as Novel p53-MDM2 Inhibitors

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