Differential Effects of Camptothecin Derivatives on Topoisomerase I-Mediated DNA Structure Modification

Wang, Xiangyang; Wang, Li Kai; Kingsbury, William D.; Johnson, Randall K.; Hecht, Sidney M.

doi:10.1021/bi980451k

Cited by 42 publications

(43 citation statements)

References 49 publications

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“…Because insertion of a hydroxyl group at the 10-position seems to enhance the stability of cleavable complexes and the antitumor activities (41,45), we thus challenge the 9-substituted lipophilic manipulation to the structure of mother compound 10-hydroxy-camptothecin. Interestingly, an allyl substitution at the 9-position enables chimmitecan a special affinity for many conventional solvents, including chloroform, glacial acetic acid, dimethylformamide, 1,4-dioxane, and methanol, permitting the formation of similar stable colloids with these solvents.…”

Section: Discussionmentioning

confidence: 99%

Chimmitecan, a Novel 9-Substituted Camptothecin, with Improved Anticancer Pharmacologic Profiles In vitro and In vivo

Huang

Gao²,

Chen

et al. 2007

Clinical Cancer Research

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Purpose: This study aimed to evaluate antitumor activities and pharmacologic profiles of chimmitecan, a novel 9-small-alkyl^substituted lipophilic camptothecin, in comparison with irinotecan (CPT-11) and topotecan. Experimental Design: The in vitro cytotoxities of chimmitecan in human tumor cell lines and multidrug resistance (MDR) cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and sulforhodamin B assays. DNA relaxation, cleavage assays, and cellular band depletion assay were combined to delineate its effects on topoisomerase I. DNA damage, cell cycle arrest, and apoptosis were assessed using comet assay, flow cytometry, and DNA ladder analysis, respectively. The in vivo antitumor activities were measured in nude mice bearing human tumor xenografts. Results: Chimmitecan displayed more potent cytotoxicity than SN38 and topotecan. Neither a cross-resistance to chimmitecan in MDR cells nor an influence of human serum albumin in its cytotoxity was observed. Chimmitecan exhibited comparable effects on topoisomerase I compared with the reference drugs, including inhibiting topoisomerase I catalytic activity and trapping and stabilizing covalent topoisomerase I-DNA complexes. Furthermore, nanomolar levels of chimmitecan caused impressive DNA damage, G 2 -M phase arrest, and apoptosis in human leukemia HL60 cells. I.v. administration of chimmitecan inhibited the growth of HCT-116, MDA-MB-435, BEL-7402, and A549 human carcinoma xenografts in nude mice, with greater potency than CPT-11 against the latter two tumors models. Chimmitecan presented potent efficacy in A549 tumor model when given orally. Conclusions: Chimmitecan is a potent inhibitor of topoisomerase I and displays outstanding activity in vitro and in vivo. The substitution at the 9-position benefits chimmitecan a salient anti-MDR activity, stability in human serum albumin, improved solubility, and oral availability, which might favorably promise its therapeutic potential in clinical settings.

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Section: Discussionmentioning

confidence: 99%

Chimmitecan, a Novel 9-Substituted Camptothecin, with Improved Anticancer Pharmacologic Profiles In vitro and In vivo

Huang

Gao²,

Chen

et al. 2007

Clinical Cancer Research

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“…DNA topoisomerases are important enzymes in the nucleus that modify the topological state of DNA through the introduction of transient breaks in the phosphodiester backbone of the DNA (Wang et al 1998). They play essential roles in mitosis, particularly in DNA transcription and replication.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure, DNA binding studies, nucleolytic property and topoisomerase I inhibition of zinc complex with 1,10-phenanthroline and 3-methyl-picolinic acid

et al. 2009

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Crystal structure analysis of the zinc complex establishes it as a distorted octahedral complex, bis(3-methylpicolinato-kappa(2) N,O)(2)(1,10-phenanthroline-kappa(2) N,N)-zinc(II) pentahydrate, [Zn(3-Me-pic)(2)(phen)]x5H(2)O. The trans-configuration of carbonyl oxygen atoms of the carboxylate moieties and orientation of the two planar picolinate ligands above and before the phen ligand plane seems to confer DNA sequence recognition to the complex. It cannot cleave DNA under hydrolytic condition but can slightly be activated by hydrogen peroxide or sodium ascorbate. Circular Dichroism and Fluorescence spectroscopic analysis of its interaction with various duplex polynucleotides reveals its binding mode as mainly intercalation. It shows distinct DNA sequence binding selectivity and the order of decreasing selectivity is ATAT > AATT > CGCG. Docking studies lead to the same conclusion on this sequence selectivity. It binds strongly with G-quadruplex with human tolemeric sequence 5'-AG(3)(T(2)AG(3))(3)-3', can inhibit topoisomerase I efficiently and is cytotoxic against MCF-7 cell line.

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“…Wang, L.K. Wang, Kingsbury, Johnson, & Hecht, 1998). However, antiviral activity results presented herein indicated that the intact E lactone ring and 20-hydroxy group are not prerequisite for camptothecin-like antiviral activity and thus conflicted with the widely accepted structure-antitumour activity relationships.…”

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confidence: 61%

Anti-HSV activity of camptothecin analogues

Liu

Tian

et al. 2010

Natural Product Research

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In order to explore the range of biological activities of the camptothecin compound class, the in vitro antiviral efficacies of series I-IV of representative members from camptothecin analogues on herpes simplex virus type 2 (HSV-2) were evaluated on vero cells. Several compounds exhibited similar or better antiviral activity against HSV-2 in vitro than acyclovir. Among them, compound 6 showed the highest anti-HSV-2 activity, with IC(50) values of 1.3 microg mL(-1) and SI values of 27.04, respectively. On the basis of preliminary biological testing results, it is suggested that the intact E lactone ring and 20-hydroxy group should be not a prerequisite for camptothecin-like antiviral activity, and CPT substitution at the C-20 hydroxy group may be optimal for synthesising more potent antiviral compounds, suggesting that CPT has the potential to be a lead structure for semi-synthetic antiviral agents.

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Differential Effects of Camptothecin Derivatives on Topoisomerase I-Mediated DNA Structure Modification

Cited by 42 publications

References 49 publications

Chimmitecan, a Novel 9-Substituted Camptothecin, with Improved Anticancer Pharmacologic Profiles In vitro and In vivo

Chimmitecan, a Novel 9-Substituted Camptothecin, with Improved Anticancer Pharmacologic Profiles In vitro and In vivo

Crystal structure, DNA binding studies, nucleolytic property and topoisomerase I inhibition of zinc complex with 1,10-phenanthroline and 3-methyl-picolinic acid

Anti-HSV activity of camptothecin analogues

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