DNA binding properties of the marine sponge pigment fascaplysin

Hörmann, Aldo; Chaudhuri, Bhabatosh; Fretz, Heinz

doi:10.1016/s0968-0896(00)00313-8

Cited by 76 publications

(46 citation statements)

References 14 publications

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“…Fascaplysin, a simple indolo-β-carboline, inhibits Cdk4-D1 kinase; however, its planar structure also renders it a DNA intercalator (25). This has inspired the synthesis of nonplanar fascaplysin analogs in an attempt to eliminate the DNA intercalating property, thereby reducing its toxicity to normal cells (26).…”

Section: Resultsmentioning

confidence: 99%

Discovery of indolotryptoline antiproliferative agents by homology-guided metagenomic screening

Chang

Brady

2013

Proc. Natl. Acad. Sci. U.S.A.

102

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Natural product discovery by random screening of broth extracts derived from cultured bacteria often suffers from high rates of redundant isolation, making it ever more challenging to identify novel biologically interesting natural products. Here we show that homology-based screening of soil metagenomes can be used to specifically target the discovery of new members of traditionally rare, biomedically relevant natural product families. Phylogenetic analysis of oxy-tryptophan dimerization gene homologs found within a large soil DNA library enabled the identification and recovery of a unique tryptophan dimerization biosynthetic gene cluster, which we have termed the bor cluster. When heterologously expressed in Streptomyces albus, this cluster produced an indolotryptoline antiproliferative agent with CaMKIIδ kinase inhibitory activity (borregomycin A), along with several dihydroxyindolocarbazole anticancer/antibiotics (borregomycins B-D). Similar homology-based screening of large environmental DNA libraries is likely to permit the directed discovery of new members within other previously rare families of bioactive natural products.antitumor | uncultured microbes | bisindole alkaloid | indenotryptoline

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Section: Resultsmentioning

confidence: 99%

Discovery of indolotryptoline antiproliferative agents by homology-guided metagenomic screening

Chang

Brady

2013

Proc. Natl. Acad. Sci. U.S.A.

102

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“…Recently another mechanism of action of 48 was determined: the murine product intercalates in double-stranded DNA, [168] a property which diminishes its therapeutic use. Nevertheless, 48 is a valuable lead structure for the developement of new CDK4,6 inhibitors.…”

Section: Paullonesmentioning

confidence: 99%

Small Molecules as Inhibitors of Cyclin‐Dependent Kinases

2003

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Cell division (mitosis) is one of the basic requirements for multicellular oranisms. The capability of a cell to replicate enables a complex assembly to be created. Faulty regulation of the control mechanism in the cell cycle leads to an excessive cell proliferation and is the cause of cancer. The key position of the cyclin-dependent kinases (CDKs) and their direct partners, as well as the fact that the majority of malign illnesses show defects in at least one of these key players of the cell cycle, is of great interest for the development of low-molecular-weight CDK inhibitors. In this Review an overview of the different structural classes of ATP-competitive inhibitors of CDKs are given, whose devlopment was aimed at battling cancer. The Review shows how far the development of selective CDK inhibitors has progressed and to what extent the expectations for such drugs have so far been fulfilled.

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“…10 However, fascaplysin is highly toxic -the potential for its planar structure to intercalate with DNA has been suggested as a possible explanation. 11 The aim of the current study is therefore to devise a potent, non-toxic (non-planar) CDK4 inhibitor based on the structure of fascaplysin.The proposed strategy (Fig. 1) is to release bonds a, b and c in fascaplysin 1 leading to the tryptamine derivative 7, this compound contains the structural components of fascaplysin, but it is nonplanar and will not intercalate with DNA.…”

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confidence: 99%