Voreloxin: DNA intercalating topoisomerase II poison

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>> Tuesday, May 18, 2010

As we know, topoisomerases are the nuclear enzymes that change the topology of DNA by transiently breaking one or two strands of DNA. They have important role in number of vital cellular processes like replication, transcription, recombination, repair, chromatin assembly, and chromosome segregation. Many anticancer drugs that target topoisomerase have been developed. For instance, Camptothecin and Etoposide, well known anticancer agents, inhibit topo I and topo II respectively.
Voreloxin, Topo II poison
Recently, Voreloxin, a quinolone derivative, which is completing phase 2 clinical trials for acute myeloid leukemia (AML) and platinum-resistant ovarian cancer, has been reported as a DNA intercalating topo II poison.
Discovery of Voreloxin has occurred while optimizing the class of compounds bearing a 1, 8 –naphthyridine core. Voreloxin has no antibacterial activity, but interestingly shows potent cytotoxicity towards eukaryotic cancer cell lines. Moreover, its activity was not affected by common mechanism of drug resistance, including P-gp overexpression, when evaluated in etoposide and anthracycline-resistant nonclinical models. Authors claimed Voreloxin as a first-in-class topo II poison and inhibitor that  intercalates DNA and induces site selective DNA DSB, G2 arrest, and apoptosis.



Structure-activity relationship (SAR) study
It was found that coplanarity of the naphthyridine core and the N-1 thiazole ring was required for antineoplastic activity. Two derivatives of Voreloxin, replacing thiazole ring with fused phenyl ring (A) and  phenyl ring (B) has been evaluated for their intercalative activity in topo I intercalation assay, using either negatively supercoiled or relaxed DNA as a substrate. It was found that phenyl derivative did not show intercalation whereas fused phenyl analog has greater DNA intercalation activity than Voreloxin. Similarly in cytotoxicity assay, phenyl derivative has weaker cytotoxicity whereas intercalative fused phenyl analogue was more cytotoxic than Voreloxin.
Voreloxin derivatives, SAR study




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