DNA-directed alkylating agents. 4. 4-Anilinoquinoline-based minor groove directed aniline mustards

Abstract

A series of 4-anilinoquinoline-linked aniline mustards of widely varying mustard reactivity were prepared and evaluated for their antitumor activity. The compounds were designed as minor grove binding agents, where the aniline mustard ring is itself part of the DNA-binding ligand. While there was a general trend for cytotoxicity to correlate with mustard reactivity, this was much less pronounced than with untargeted mustards. The compounds were much more cytotoxic than the parent diols, and were also at least 10-fold more cytotoxic than the corresponding aniline mustards themselves. Comparative cell line studies suggested that the mechanism of cytotoxicity varied with mustard reactivity. The most reactive mustards cross-linked DNA, while cell killing by the less reactive compounds appeared to be by the formation of bulky monoadducts. The compounds were active but not particularly dose-potent against P388 leukemia in vivo. The modest potency may be related to their poor aqueous solubility, since the more soluble methyl quaternary salts were equally active at much lower doses.

Synthesis and in vitro cytotoxicity of 9-anilinoacridines bearing N-mustard residue on both anilino and acridine rings

“…Intermediates, 9-chloroacridines (7) and aniline-N-mustard conjugates (8), were prepared by following the procedure previously developed in our laboratory [13,14]. Synthesis of conjugates 9-13 having N-mustard residues on both anilino and acridine rings was achieved by the reaction of freshly prepared 9-chloroacridines (7a,b) with anilines (8a, 8b, 8c and 8d) in ethanol at À5 C. After completion of the reaction, the desired products were purified by column chromatography.…”

Synthesis and in vitro cytotoxicity of 9-anilinoacridines bearing N-mustard residue on both anilino and acridine rings

“…Intermediates, 9-chloroacridines (7) and aniline-N-mustard conjugates (8), were prepared by following the procedure previously developed in our laboratory [13,14]. Synthesis of conjugates 9-13 having N-mustard residues on both anilino and acridine rings was achieved by the reaction of freshly prepared 9-chloroacridines (7a,b) with anilines (8a, 8b, 8c and 8d) in ethanol at À5 C. After completion of the reaction, the desired products were purified by column chromatography.…”

Sequence specificity of the binding of 9-aminoacridine- and amsacrine-4-carboxamides to DNA studied by DNase I footprinting

“…Compounds such as the amsacrine-4-carboxamides that are able to place distinguishable side chains selectively in each DNA groove in a well-defined fashion may have important potential as templates for the specific delivery of other, reactive, functional groups to defined regions of DNA [see, for example, Prakash et al (1990) and Gourdie et al (1991)]. In a similar vein AT-specific minor groove binding ligands bearing such reactive groups also hold out the prospect of more selectively toxic antitumor agents (Gravatt et al, 1991). Lastly, we note that the combination of strongly GC-selective intercalators and AT-specific groove binders may provide a route to the design of ligands targeted to defined sequences [see, for example, Bailly et al, (1990a)].…”

Acylation Reactions under Microwaves. 3. Aroylation of Benzene and Its Slightly Activated or Deactivated Derivatives

“…All reagents ( 1 − 14 ) and catalysts were purchased (high-grade purity) and used without purification. The products 15 − 29 were identified and their isomeric compositions were determined by comparison of their spectral data (NMR, GC-MS) with those of authentic samples: 15 , 28 (from Aldrich), 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25, 26, 27, 29 42 . GC: Hewlett-Packard 6890 chromatograph equipped with a 30-m × 0.32-mm column (methyl silicone doped with 5% phenyl silicone, 0.25 μm).…”

Synthesis and in vitro cytotoxicity of 9-anilinoacridines bearing N-mustard residue on both anilino and acridine rings

“…Intermediates, 9-chloroacridines (7) and aniline-N-mustard conjugates (8), were prepared by following the procedure previously developed in our laboratory [13,14]. Synthesis of conjugates 9-13 having N-mustard residues on both anilino and acridine rings was achieved by the reaction of freshly prepared 9-chloroacridines (7a,b) with anilines (8a, 8b, 8c and 8d) in ethanol at À5 C. After completion of the reaction, the desired products were purified by column chromatography.…”

Sequence specificity of the binding of 9-aminoacridine- and amsacrine-4-carboxamides to DNA studied by DNase I footprinting

“…Compounds such as the amsacrine-4-carboxamides that are able to place distinguishable side chains selectively in each DNA groove in a well-defined fashion may have important potential as templates for the specific delivery of other, reactive, functional groups to defined regions of DNA [see, for example, Prakash et al (1990) and Gourdie et al (1991)]. In a similar vein AT-specific minor groove binding ligands bearing such reactive groups also hold out the prospect of more selectively toxic antitumor agents (Gravatt et al, 1991). Lastly, we note that the combination of strongly GC-selective intercalators and AT-specific groove binders may provide a route to the design of ligands targeted to defined sequences [see, for example, Bailly et al, (1990a)].…”

Acylation Reactions under Microwaves. 3. Aroylation of Benzene and Its Slightly Activated or Deactivated Derivatives

“…All reagents ( 1 − 14 ) and catalysts were purchased (high-grade purity) and used without purification. The products 15 − 29 were identified and their isomeric compositions were determined by comparison of their spectral data (NMR, GC-MS) with those of authentic samples: 15 , 28 (from Aldrich), 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25, 26, 27, 29 42 . GC: Hewlett-Packard 6890 chromatograph equipped with a 30-m × 0.32-mm column (methyl silicone doped with 5% phenyl silicone, 0.25 μm).…”

Synthesis and in vitro cytotoxicity of 9-anilinoacridines bearing N-mustard residue on both anilino and acridine rings

“…Intermediates, 9-chloroacridines (7) and aniline-N-mustard conjugates (8), were prepared by following the procedure previously developed in our laboratory [13,14]. Synthesis of conjugates 9-13 having N-mustard residues on both anilino and acridine rings was achieved by the reaction of freshly prepared 9-chloroacridines (7a,b) with anilines (8a, 8b, 8c and 8d) in ethanol at À5 C. After completion of the reaction, the desired products were purified by column chromatography.…”

Sequence specificity of the binding of 9-aminoacridine- and amsacrine-4-carboxamides to DNA studied by DNase I footprinting

“…Compounds such as the amsacrine-4-carboxamides that are able to place distinguishable side chains selectively in each DNA groove in a well-defined fashion may have important potential as templates for the specific delivery of other, reactive, functional groups to defined regions of DNA [see, for example, Prakash et al (1990) and Gourdie et al (1991)]. In a similar vein AT-specific minor groove binding ligands bearing such reactive groups also hold out the prospect of more selectively toxic antitumor agents (Gravatt et al, 1991). Lastly, we note that the combination of strongly GC-selective intercalators and AT-specific groove binders may provide a route to the design of ligands targeted to defined sequences [see, for example, Bailly et al, (1990a)].…”

Acylation Reactions under Microwaves. 3. Aroylation of Benzene and Its Slightly Activated or Deactivated Derivatives

“…All reagents ( 1 − 14 ) and catalysts were purchased (high-grade purity) and used without purification. The products 15 − 29 were identified and their isomeric compositions were determined by comparison of their spectral data (NMR, GC-MS) with those of authentic samples: 15 , 28 (from Aldrich), 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25, 26, 27, 29 42 . GC: Hewlett-Packard 6890 chromatograph equipped with a 30-m × 0.32-mm column (methyl silicone doped with 5% phenyl silicone, 0.25 μm).…”