385d › Citations

Degradation of the morpholino ring in the crystal structure of cyanomorpholinodoxorubicin complexed with d(CGATCG).

Ettorre A, Cirilli M, Ughetto G
Eur J Biochem 258 350-4 (1998)
Cited: 24 times
EuropePMC logo PMID: 9874199

Abstract

The cyanomorpholino analogue of antitumor anthracycline doxorubicin possesses an intense potency and differs from the parent compound in cross-resistance and other biological properties. The induction by cyanomorpholinodoxorubicin of both DNA cross-links and strand scission suggests an altered mode of action relative to doxorubicin with a different DNA-interacting capacity. We have co-crystallized 3'-(3-cyano-4-morpholinyl)-3'-desaminodoxorubicin (CMD) with the DNA hexamer d(CGATCG) and have determined the crystal structure at 0.16-nm resolution. The complex crystallizes in the space group P4(1)2(1)2 and is similar to the previously reported anthracycline/DNA structures, with the drug intercalated at the CpG step, forming hydrogen bonds with the guanine residue. The structure reveals that the morpholino moiety has undergone a major rearrangement with loss of the cyano group and opening of the morpholino ring. The compound actually bound to DNA in the complex resembles N-(2-hydroxyethyl)doxorubicin, which was previously identified as a hydrolysis product of CMD. No DNA alkylation has been observed. However, the structure shows that the active site of the morpholino ring, after dissociation of the cyano group, lies in the minor groove in proximity of the A/T base pair. This may indicate that a C/G base pair next to the intercalation site, with NH2 group in the minor groove, is required for DNA alkylation.

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  2. Modulation of the osteosarcoma expression phenotype by microRNAs. Namløs HM, Meza-Zepeda LA, Barøy T, Østensen IH, Kresse SH, Kuijjer ML, Serra M, Bürger H, Cleton-Jansen AM, Myklebost O. PLoS One 7 e48086 (2012)
  3. DNA conformations and their sequence preferences. Svozil D, Kalina J, Omelka M, Schneider B. Nucleic Acids Res. 36 3690-3706 (2008)
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  6. Unraveling the sequence-dependent polymorphic behavior of d(CpG) steps in B-DNA. Dans PD, Faustino I, Battistini F, Zakrzewska K, Lavery R, Orozco M. Nucleic Acids Res. 42 11304-11320 (2014)
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  13. Genome-wide transcriptome analysis of hypothalamus in rats with inherited stress-induced arterial hypertension. Klimov LO, Ershov NI, Efimov VM, Markel AL, Redina OE. BMC Genet. 17 Suppl 1 13 (2016)
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Reviews citing this publication (1)

  1. Anthracycline drug targeting: cytoplasmic versus nuclear--a fork in the road. Lothstein L, Israel M, Sweatman TW. Drug Resist. Updat. 4 169-177 (2001)

Articles citing this publication (2)

  1. Phenazine-1-carboxamides: structure-cytotoxicity relationships for 9-substituents and changes in the H-bonding pattern of the cationic side chain. Gamage SA, Rewcastle GW, Baguley BC, Charlton PA, Denny WA. Bioorg. Med. Chem. 14 1160-1168 (2006)
  2. Release of the cyano moiety in the crystal structure of N-cyanomethyl-N-(2-methoxyethyl)-daunomycin complexed with d(CGATCG). Saminadin P, Dautant A, Mondon M, Langlois D'estaintot B, Courseille C, Précigoux G. Eur. J. Biochem. 267 457-464 (2000)


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