NOVEL ACRIDINE-TRIAZENES AS PROTOTYPE COMBILEXINS - SYNTHESIS, DNA-BINDING, AND BIOLOGICAL-ACTIVITY

被引:124
作者
MCCONNAUGHIE, AW [1 ]
JENKINS, TC [1 ]
机构
[1] INST CANC RES, CANC RES CAMPAIGN, BIOMOLEC STRUCT UNIT, SUTTON SM2 5NG, SURREY, ENGLAND
关键词
D O I
10.1021/jm00018a009
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of bifunctional ligands has been developed as prototype DNA-binding combilexins using a DNA template-directed approach. These novel agents contain a 1,3-diaryltriazene linker moiety, present in the established DNA minor groove-binder berenil [1,3-bis(4'-amidinophenyl)triazene], which is attached to an intercalating acridine chromophore by a functionalized thiazole residue. This 9-arylacridine is predicted to confer rotational freedom to the hybrid molecule and thus facilitate bifunctional interaction with double-stranded DNA through a combination of 'classical' intercalation and minor groove-binding processes. The noncovalent DNA-binding properties of these acridine-triazene combilexins, together with the component molecular fragments, have been examined by fluorescence quenching and thermal denaturation studies with calf thymus DNA and two oligonucleotides, [poly(dA-dT)](2) and [poly(dG-dC)](2). In addition, the binding behaviors of these acridine compounds are compared to those of proflavine (3,6-diaminoacridine) and its 9-phenyl derivative. The results indicate that the hybrid agents (i) are more DNA-affinic than either molecular component, (ii) retain the AT-preferential binding properties of the parent difunctionalized 1,3-diaryltriazene residues, despite weak GC-preferential behavior associated with the acridine chromophore, and (iii) have a reduced binding affinity at pH 7 that reflects the protonation status of the acridine. In contrast, the more basic proflavines show much greater binding affinity and a marked preference for GC-rich DNA sequences. In vitro cytotoxicity data with L1210 mouse leukemia and A2780 human colon cancer cell lines show that the conjugate molecules are similar to 10-40-fold more potent than the acridine or triazene subunits and have activities that compare favorably with those of other reported synthetic combilexins. Intercalative binding modes with a model d(GATACGATAC). d(GTATCGTATC) target duplex have been investigated using molecular modeling techniques. These studies provide a rational basis for the binding properties and suggest that the prototype combilexins can bind in a bimodal manner that induces little distortion of the host DNA duplex. Energy-minimized models for the possible dual interactions are discussed.
引用
收藏
页码:3488 / 3501
页数:14
相关论文
共 53 条
[11]   CRYSTAL-STRUCTURE OF A BERENIL-D(CGCAAATTTGCG) COMPLEX - AN EXAMPLE OF DRUG DNA RECOGNITION BASED ON SEQUENCE-DEPENDENT STRUCTURAL FEATURES [J].
BROWN, DG ;
SANDERSON, MR ;
GARMAN, E ;
NEIDLE, S .
JOURNAL OF MOLECULAR BIOLOGY, 1992, 226 (02) :481-490
[12]   CRYSTAL-STRUCTURE OF A BERENIL DODECANUCLEOTIDE COMPLEX - THE ROLE OF WATER IN SEQUENCE-SPECIFIC LIGAND-BINDING [J].
BROWN, DG ;
SANDERSON, MR ;
SKELLY, JV ;
JENKINS, TC ;
BROWN, T ;
GARMAN, E ;
STUART, DI ;
NEIDLE, S .
EMBO JOURNAL, 1990, 9 (04) :1329-1334
[13]   A BIFURCATED HYDROGEN-BONDED CONFORMATION IN THE D(A.T) BASE-PAIRS OF THE DNA DODECAMER D(CGCAAATTTGCG) AND ITS COMPLEX WITH DISTAMYCIN [J].
COLL, M ;
FREDERICK, CA ;
WANG, AHJ ;
RICH, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (23) :8385-8389
[14]   INTERACTION OF MINOR-GROOVE-BINDING DIAMIDINE LIGANDS WITH AN ASYMMETRIC DNA DUPLEX NMR AND MOLECULAR MODELING STUDIES [J].
CONTE, MR ;
JENKINS, TC ;
LANE, AN .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1995, 229 (02) :433-444
[15]  
CROOKE ST, 1993, ANTISENSE RES APPLIC
[16]   DESIGN OF SEQUENCE-SPECIFIC DNA-BINDING MOLECULES [J].
DERVAN, PB .
SCIENCE, 1986, 232 (4749) :464-471
[17]   THE SYNTHESIS AND DNA FOOTPRINTING OF ACRIDINE-LINKED NETROPSIN AND DISTAMYCIN BIFUNCTIONAL MIXED-LIGANDS [J].
ELIADIS, A ;
PHILLIPS, DR ;
REISS, JA ;
SKOROBOGATY, A .
JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1988, (15) :1049-1052
[18]   INTERACTIONS OF ANTITUMOR DRUGS WITH NATURAL DNA - H-1-NMR STUDY OF BINDING MODE AND KINETICS [J].
FEIGON, J ;
DENNY, WA ;
LEUPIN, W ;
KEARNS, DR .
JOURNAL OF MEDICINAL CHEMISTRY, 1984, 27 (04) :450-465
[19]  
FREEMONT PS, 1991, BIOCHEM J, V278, P1
[20]   ISOHELICAL ANALYSIS OF DNA GROOVE-BINDING DRUGS [J].
GOODSELL, D ;
DICKERSON, RE .
JOURNAL OF MEDICINAL CHEMISTRY, 1986, 29 (05) :727-733