The antileukemic alkaloid fagaronine is an inhibitor of DNA topoisomerases I and II

Larsen, Annette K.; Grondard, Lucile; Couprie, Jeannine; Desoize, B; Comoe, L; Jardillier, Jean‐Claude; Riou, Jean‐François

doi:10.1016/0006-2952(93)90105-6

Cited by 117 publications

(77 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nitidine and its sister alkaloid fagaronine have recently been shown to be topoisomerase inhibitors (4,8); thus, it is possible that the antimalarial action is mediated through the inhibition of the parasite enzyme. If this is the case, analogs which bind preferentially to the parasite enzyme may represent a source of new antimalarial drugs, and we are pursuing this.…”

Section: Discussionmentioning

confidence: 99%

Potent antimalarial activity of the alkaloid nitidine, isolated from a Kenyan herbal remedy

Gakunju

Mberu

Dossaji

et al. 1995

Antimicrob Agents Chemother

116

View full text Add to dashboard Cite

Bioassay-guided fractionation of extracts of Toddalia asiatica, a plant used by the Pokot tribe of Kenya to treat fevers, has yielded the alkaloid nitidine as the major antimalarial component. Fractions containing nitidine have in vitro 50% inhibitory concentrations against Plasmodium falciparum in the range of 9 to 108 ng/ml for a range of chloroquine-susceptible and -resistant strains. The results show a lack of cross-resistance between chloroquine and nitidine.Although malaria is in principle preventable and curable, in practice the majority of the population at risk cannot pay for modern treatment and the disease remains a major cause of childhood mortality in the developing world. Recent results with the vaccine sPf66 show a mean protective effect of only 30%, with very wide confidence limits (1). The rapid spread of resistance to chloroquine and related quinoline-based antimalarial agents has greatly increased the risk of malaria to many rural populations, so that there is an urgent need for affordable treatment. One possible source of such treatment lies in the traditional herbal remedies used by ethnic groups, but treatment with these remedies has suffered from a number of deficiencies. Diagnosis is often a problem, identification of plant material may be insecure, and the chemical content of extracts may vary considerably. We have set out to overcome these barriers to effective treatment by systematically evaluating the effectiveness of some of the remedies used by an ethnic group of Kenyan farmers.The Pokot traditionally inhabit a highland plateau, west of the Rift Valley in Kenya. However, the present study concerned a group of Pokot who live on Ol Ari Nyiro Ranch, Laikipia, Kenya, a plateau to the east of the Rift Valley, and who have previously been described in some detail (5).In interviews, the Pokot herbalist Cheptosai Selale, who is 90 years old, described the use of 26 plants for the treatment of malaria and fever, of which only 14 were available at the time of collection (see Table 1). Two of the 14 plants produced extracts with significant antimalarial activity against laboratory strains of Plasmodium falciparum. Bioassay-guided fractionation of the extract from Toddalia asiatica gave a pure alkaloid, nitidine, which has potentially useful antimalarial activity. MATERIALS AND METHODSPlant material. Plant material was collected from Ol Ari Nyiro Ranch and was botanically authenticated by Christine Kabuye and Joshua Muasya of the Herbarium, National Museums of Kenya, where voucher specimens were deposited. Information provided by the herbalist included the required part of the plant, the precise locality for collection, and the time when curative potency was maximal. Plant material for study was dried at room temperature, pulverized, and stored dry in plastic bags until extracts were obtained.Preparation of aqueous crude extracts for preliminary analysis. Aqueous crude extracts (10%) were prepared in a manner analogous to that used by the herbalist. Powdered plant material (10 g) was weighed in...

show abstract

Section: Discussionmentioning

confidence: 99%

Potent antimalarial activity of the alkaloid nitidine, isolated from a Kenyan herbal remedy

Gakunju

Mberu

Dossaji

et al. 1995

Antimicrob Agents Chemother

116

View full text Add to dashboard Cite

show abstract

“…On the other hand, phenanthroline, azaindolizine and phenanthridine derivatives were successful identified as DNA intercalating agents or possessing antimycobacterial activity 26,30,[40][41][42][43] . In the same time, benzo[c]phenanthridinium alkaloids as fagaronine and nitidine which showed antileukemic activity on rodents 44 and act as topoisomerase I and II inhibitors [45][46][47] , played the role of model compound for the development of new anticancer agents 14 . Having all these above consideration in mind and encouraged by our previous promising results in the field of anti-TB [25][26][27][28] and anticancer 29,30,32 derivatives with indolizine and/or phenanthroline skeleton, we have focused on the design of novel structures that contain four or five fused (hetero)cycles with pyrrolo[2,1-c] [4,7]phenanthroline skeleton (Scheme 3).…”

Section: Chemistrymentioning

confidence: 99%

Synthesis, structure, antimycobacterial and anticancer evaluation of new pyrrolo-phenanthroline derivatives

Matarneh

Mangalagiu

Shova³

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

A study concerning design, synthesis, structure and in vitro antimycobacterial and anticancer evaluation of new fused derivatives with pyrrolo[2,1-c] [4,7]phenanthroline skeleton is described. The strategy adopted for synthesis involves a [3 + 2] dipolar cycloaddition of several in situ generated 4,7-phenanthrolin-4-ium ylides to different substituted alkynes and alkenes. Stereo-and regiochemistry of cycloaddition reactions were discussed. The structure of the new compounds was proven unambiguously, single-crystal X-ray diffraction studies including. The antimycobacterial and anticancer activity of a selection of new synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv under aerobic conditions and 60 human tumour cell line panel, respectively. Five of the tested compounds possess a moderate antimycobacterial activity, while two of the compounds have a significant antitumor activity against renal cancer and breast cancer.

show abstract

“…A limited number of dual topoisomerase inhibitors have been identified and some are being developed as anticancer agents. These include the anthracycline-like anthraquinone saintopin, indenoquinolones (TAS-103), quaternary alkaloids ( fagaronine), the indolocarbazole NB-506, GA3P polysaccharide, the acridine DACA and pyrazoloacridine, the pyridoindole intoplicin, XR5944, and the homocamptothecin derivative BN-80297 (32)(33)(34)(35)(36)(37)(38)(39)(40). The DPCs produced by batracylin had a significantly longer half-life than those induced by VP-16 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Batracylin (NSC 320846), a Dual Inhibitor of DNA Topoisomerases I and II Induces Histone γ-H2AX as a Biomarker of DNA Damage

et al. 2007

View full text Add to dashboard Cite

Batracylin (8-aminoisoindolo [1,2-b]quinazolin-10(12H)-one; NSC320846) is an investigational clinical anticancer agent. Previous animal studies showed activity against solid tumors and Adriamycin-resistant leukemia. We initially sought to test the proposed Top2-mediated DNA cleavage activity of batracylin and identify potential biomarkers for activity. COMPARE analysis in the NCI-60 cell lines showed batracylin activity to be most closely related to the class of Top2 inhibitors. The 50% growth inhibition (GI 50 ) value for batracylin in HT29 colon carcinoma cells was 10 Mmol/L. DNA-protein cross-links, consistent with Top2 targeting, were measured by alkaline elution. DNA single-strand breaks were also detected and found to be protein associated. However, only a weak induction of DNA double-strand breaks was observed. Because batracylin induced almost exclusively DNA single-strand breaks, we tested batracylin as a Top1 inhibitor. Batracylin exhibited both Top1-and Top2A/B-mediated DNA cleavage in vitro and in cells. The phosphorylation of histone (;-H2AX) was tested to measure the extent of DNA damage. Kinetics of ;-H2AX ''foci'' showed early activation with low Mmol/L concentrations, thus presenting a useful early biomarker of DNA damage. The halflife of ;-H2AX signal reversal after drug removal was consistent with reversal of DNA-protein cross-links. The persistence of the DNA-protein complexes induced by batracylin was markedly longer than by etoposide or camptothecin. The phosphorylated DNA damage-responsive kinase, ataxia telangiectasia mutated, was also found activated at sites of ;-H2AX. The cell cycle checkpoint kinase, Chk2, was only weakly phosphorylated. Thus, batracylin is a dual Top1 and Top2 inhibitor and ;-H2AX could be considered a biomarker in the ongoing clinical trials. [Cancer Res 2007;67(20):9971-9]

show abstract

The antileukemic alkaloid fagaronine is an inhibitor of DNA topoisomerases I and II

Cited by 117 publications

References 29 publications

Potent antimalarial activity of the alkaloid nitidine, isolated from a Kenyan herbal remedy

Potent antimalarial activity of the alkaloid nitidine, isolated from a Kenyan herbal remedy

Synthesis, structure, antimycobacterial and anticancer evaluation of new pyrrolo-phenanthroline derivatives

Batracylin (NSC 320846), a Dual Inhibitor of DNA Topoisomerases I and II Induces Histone γ-H2AX as a Biomarker of DNA Damage

Contact Info

Product

Resources

About