Water soluble derivatives of rebeccamycin.

Kaneko, Takushi; Wong, Henry; Utzig, Jacob; Schurig, John E.; Doyle, Terrence W.

doi:10.7164/antibiotics.43.125

Cited by 50 publications

(21 citation statements)

References 5 publications

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“…2) Protein kinases and DNA topoisomerases are important in cell proliferation, so speciˆc inhibitors are promising candidates for antitumor drugs. In fact, UCN-01, 3) BMY-27557, 4) and J-109384 5) are indolocarbazoles now in clinical trials for cancer chemotherapy.…”

Section: Characterization Of the Biosynthetic Gene Cluster Ofmentioning

confidence: 98%

“…UV-visible spectra were taken on a HP1090 system. NMR data for compounds 4,5,8,9,10, and 11 are shown in Tables 1 to 3 Bioconversion experiments. Two hundred mg of a putative puriˆed intermediate was added to a tube containing 10 ml of medium G134 and already cultured L. aerocolonigenes rebH ::km r was used to inoculate the same tube.…”

Section: Puriˆcation Of Rebeccamycin Intermediatesmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of the Biosynthetic Gene Cluster of Rebeccamycin fromLechevalieria aerocolonigenesATCC 39243

Onaka¹,

Taniguchi²,

Igarashi³

et al. 2003

Bioscience, Biotechnology, and Biochemistry

112

124

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The biosynthetic gene cluster for rebeccamycin, an indolocarbazole antibiotic, from Lechevalieria aerocolonigenes ATCC 39243 has 11 ORFs. To clarify their functions, mutants with rebG, rebD, rebC, rebP, rebM, rebR, rebH, rebT, or orfD2 disrupted were constructed, and the gene products were examined. rebP disruptants produced 11,11'-dichlorochromopyrrolic acid, found to be a biosynthetic intermediate by a bioconversion experiment. Other genes encoded N-glycosyltransferase (rebG), monooxygenase (rebC), methyltransferase (rebM), a transcriptional activator (rebR), and halogenase (rebH). rebT disruptants produced rebeccamycin as much as the wild strain, so rebT was probably not involved in rebeccamycin production. Biosynthetic genes of staurosporine, an another indolocarbazole antibiotic, were cloned from Streptomyces sp. TP-A0274. staO, staD, and staP were similar to rebO, rebD, and rebP, respectively, all of which are responsible for indolocarbazole biosynthesis, But a rebC homolog, encoding a putative enzyme oxidizing the C-7 site of pyrrole rings, was not found in the staurosporine biosynthetic gene cluster. These results suggest that indolocarbazole is constructed by oxidative decarboxylation of chromopyrrolic acid (11,11'-dichlorochromopyrrolic acid in rebeccamycin) generated from two molecules of tryptophan by coupling and that the oxidation state at the C-7 position depends on the additional enzyme(s) encoded by the biosynthetic genes.

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Section: Characterization Of the Biosynthetic Gene Cluster Ofmentioning

confidence: 98%

Section: Puriˆcation Of Rebeccamycin Intermediatesmentioning

confidence: 99%

Characterization of the Biosynthetic Gene Cluster of Rebeccamycin fromLechevalieria aerocolonigenesATCC 39243

Onaka¹,

Taniguchi²,

Igarashi³

et al. 2003

Bioscience, Biotechnology, and Biochemistry

112

124

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“…Rebeccamycin, the parent compound has demonstrated impressive activity against P388 leukemia, L1210 leukemia, B16 melanoma, human lung adenocarcinoma cells (A549) and HCT 116 colon carcinoma. Since rebeccamycin is insoluble in water, the water-soluble tartrate salt of rebeccamycin NSC 655649 has been created [11]. Rebeccamycin inhibits topoisomerase II strand passing ability by intercalating DNA without stabilization of the cleavable complex intermediate.…”

Section: Introductionmentioning

confidence: 99%

Randomized phase II trial of different schedules of administration of rebeccamycin analogue as second line therapy in non-small cell lung cancer

Dowlati

Chapman²,

Subbiah

et al. 2005

Invest New Drugs

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Rebeccamcyin analogue (RA) is an antitumor antibiotic that results in DNA intercalation and topoisomerase I and II inhibition. Phase I trials of the daily x 5 schedule and once every 3 week schedule have been completed. Antitumor activity was observed during the phase I trials. The purpose of this study is to primarily determine the response rate of 2 different schedules of administration of RA in patients with advanced non-small cell lung cancer (NSCLC) who had progressed on one prior chemotherapy regimen. Secondary endpoints were median and 1-year survival rates. A two-stage Simon design was employed for both arms of the study. Patients were randomly assigned to either of two RA treatment schedules of 500 mg/m(2) as a 1 hr infusion repeated every 3 weeks (Arm A) or 140 mg/m(2)/day x 5 days repeated every 3 weeks (Arm B). Forty-two patients were randomized. No confirmed objective responses were seen. Stable disease was seen in 52% of patients on arm A and 37% on arm B. Median survival and 1 year survival rates were 5.6 months and 33.3% for arm A, 9.7 months and 42.1% for arm B respectively. Cox regression model demonstrated increased risk of death in patients younger than the age of 61 and for patients treated on arm A. RA failed to demonstrate a significant response rate in this disease setting, although the proportion of patients with stable disease and 1-year survival were encouraging and similar to other published studies of approved single agents for second-line therapy of NSCLC.

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“…[ 26] In a 1990 paper by Kaneko et al, the rebeccamycin analogue NSC 655649 (later known as becatecarin, Figure 7) was synthesised as a water-soluble derivative of rebeccamycin, [27] a natural product and topoisomerase I inhibitor first isolated and characterised in 1985. [28,29] Becatecarin is an indolocarbazole, like edotecarin ( Figure 6), and indeed has a remarkably similar structure.…”

Section: Topoisomerase Inhibitorsmentioning

confidence: 99%

“…During in vitro studies, becatecarin was shown to be active against cell lines of Ewing sarcoma, medulloblastoma, neuroblastoma and rhabdomyosarcoma, [30] and it appeared to be a more potent anticancer drug than rebeccamycin itself when tested on a leukaemia cell line. [27] A range of promising Phase I clinical trials were carried out on becatecarin between 1996 and 2002, [31][32][33][34][35][36] but in a 2008 Phase II clinical study by Langevin et al on the effects of the drug on children with solid CNS tumours, it was revealed that myelosupression was a significant side effect, [37] effectively halting the development of this drug for use on this demographic.…”

Section: Topoisomerase Inhibitorsmentioning

confidence: 99%

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

Sherer

Snape

2015

European Journal of Medicinal Chemistry

133

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HIGHLIGHTS• Brain cancer mortality rates are much higher than mortality rates for cancers of other sites. •Due to the blood brain barrier, many drugs that work on cancers of other sites do not work on brain cancers • Indoles, carbazoles and indolocarbazoles make good scaffolds for drugs to be built up around due to their rigidity, planarity and ease of synthesis. GRAPHICAL ABSTRACT ACRONYMS/INITIALISMSAML -Acute myeloid leukaemia CK2 -Casein kinase 2 CNS -Central nervous system PARP -Poly ADP ribose polymerase PDGF -Platelet-derived growth factor PKC -Protein kinase C ROS -Reactive oxygen species VEGF -Vascular endothelial growth factor ABSTRACT Tumours of the central nervous system are intrinsically more dangerous than tumours at other sites, and in particular, brain tumours are responsible for 3% of cancer deaths in the UK. Despite this, research into new therapies only receives 1% of national cancer research spend. The most common chemotherapies are temozolomide, procarbazine, carmustine, lomustine and vincristine, but because of the rapid development of chemoresistance, these drugs alone simply aren't sufficient for longterm treatment. Such poor prognosis of brain tumour patients prompted us to research new treatments for malignant glioma, and in doing so, it became apparent that aromatic heterocycles play an important part, especially the indole, carbazole and indolocarbazole scaffolds. This review highlights compounds in development for the treatment of tumours of the central nervous system which are structurally based on the indole, carbazole and indolocarbazole scaffolds, under the expectation that it will highlight new avenues for research for the development of new compounds to treat these devastating neoplasms.

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Water soluble derivatives of rebeccamycin.

Cited by 50 publications

References 5 publications

Characterization of the Biosynthetic Gene Cluster of Rebeccamycin fromLechevalieria aerocolonigenesATCC 39243

Characterization of the Biosynthetic Gene Cluster of Rebeccamycin fromLechevalieria aerocolonigenesATCC 39243

Randomized phase II trial of different schedules of administration of rebeccamycin analogue as second line therapy in non-small cell lung cancer

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

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