Spectroscopic Investigation on the Interaction of NCA0424, a Potent Antitumor Indoloquinoxaline Derivative, with DNA

NCA0424 (1), an indoloquinoxaline derivative, has a potent antitumor activity against in vitro and in vivo tumor models. To elucidate its structure-activity relationship, the interactions with various B-form DNAs were investigated by thermal denaturation, viscosity and circular dichroism (CD) measur...

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Bibliographic Details
Published in:	Chemical & pharmaceutical bulletin Vol. 46; no. 5; pp. 739 - 743
Main Authors:	ISHIDA, Toshimasa, MIHARA, Yoshitetsu, HAMA, Yumiko, HANATANI, Akemi, TARUI, Mariko, DOI, Mitsunobu, NAKAIKE, Shiro, KITAMURA, Kunihiro
Format:	Journal Article
Language:	English
Published:	Tokyo The Pharmaceutical Society of Japan 01-05-1998 Maruzen Japan Science and Technology Agency
Subjects:	Antineoplastic agents Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Biological and medical sciences Circular Dichroism DNA DNA - chemistry DNA - drug effects General aspects Indoles - chemistry Indoles - pharmacology indoloquinoxaline induced CD Intercalating Agents - pharmacology intercalation Medical sciences Nucleic Acid Denaturation Pharmacology. Drug treatments Quinoxalines - chemistry Quinoxalines - pharmacology Spectrophotometry, Ultraviolet thermal stability Viscosity Antineoplastic agent Circular dichroism spectrum Sequence specificity Aminoalcohol Nitrogen heterocycle Molecular interaction Tetracyclic compound Duplex Thermal stability Biological fixation DNA Molecular intercalation Aromatic compound Viscosimetry Mechanism of action
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Summary:	NCA0424 (1), an indoloquinoxaline derivative, has a potent antitumor activity against in vitro and in vivo tumor models. To elucidate its structure-activity relationship, the interactions with various B-form DNAs were investigated by thermal denaturation, viscosity and circular dichroism (CD) measurements. The thermal stability of the DNA duplex was increased by the interaction with 1, and preferable binding for alternative purine-pyrimidine base sequence was suggested. Comparative viscometric measurements with ethidium bromide (an intercalator) and distamycin (a minor groove binder) suggested that 1 is an intercalator. The interaction of DNA with 1 revealed a new CD band at 340-390 nm. Taking advantage of this induced CD band, the equilibrium binding constants were determined for various DNAs, and the binding preference of 1 for the alternative purine-pyrimidine base sequence, especially for the case of guanine as purine base, was indicated. The appearance of the induced CD band implies the importance of 1 side chain for the effective and/or stable intercalation of the aromatic ring into the DNA base pair.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0009-2363 1347-5223
DOI:	10.1248/cpb.46.739