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At least 91 records · Page 5Linked to original sources
PubMed1986

Conformations of complexes between pyrrolo[1,4]benzodiazepines and DNA segments.

The molecular mechanics program AMBER, assisted by CHEMLAB II, was used to model the covalent and noncovalent binding of anthramycin, tomaymycin, and neothramycin A to the hexanucleotide conformation. Structures covalently bonded at N2 of guanine gave excellent fits when placed in either direction in the minor groove. However, energy analysis showed a preference for the direction wherein the side chain points toward the 5' end of the covalently bound strand. This preference agrees with published NMR studies. Noncovalent binding of anthramycin in the minor groove near guanine gave good fits with almost no distortion in the helix, and the reactive center of the ligand was close enough to N2 for subsequent covalent bond formation. Anthramycin also gave a good noncovalent complex near adenine in the minor groove, but binding in the major groove had decreased dispersion attractions. Binding of tomaymycin was similar to that of anthramycin, although the smaller size of tomaymycin resulted in less binding energy. Neothramycin noncovalent binding was characterized by strong electrostatic interactions, partly involving the 3-OH group, and by part of the molecule lying outside the minor groove. AMBER was used for the exploratory design of an anthramycin analogue that theoretically would bind as well as anthramycin but not cause cardiotoxicity. A related study involving anthramycin, tomaymycin, and the pentanucleotide duplex d(AAGAA/TTCTT) was undertaken to evaluate further the ability of AMBER to predict sequence specificity. It indicated a preferred direction of binding toward 5' in the minor groove of the duplex, but rather weak interaction with the noncovalently bound strand. This prediction agreed with experiments on tomaymycin that showed separation of the duplex and alignment of the drug toward the 5' end of the covalently bound strand.

Anthramycin↗
PubMed1996

DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata.

Ecteinascidin 743 is one of several related marine alkaloids isolated from the Caribbean tunicate Ecteinascidia turbinata. It is remarkably active and potent in a variety of in vitro and in vivo systems and has been selected for development as an anticancer agent. The present study investigates the interactions of ecteinascidin 743 with DNA. Ecteinascidin 743 retarded the electrophoretic migration of both supercoiled and relaxed simian virus 40 DNA even in the presence of sodium dodecyl sulfate and after ethanol precipitation, consistent with covalent DNA modifications. Similar results were obtained in a DNA oligonucleotide derived from ribosomal DNA. However, DNA denaturation reversed the DNA modifications. The homopolymeric oligonucleotide dG/dC was modified while neither the dI/dC nor the dA/dT oligonucleotides were, consistent with covalent attachment of ecteinascidin 743 to the exocyclic amino group at position 2 of guanine. Ecteinascidin 743 was then compared to another known DNA minor groove alkylating agent, anthramycin, which has also been shown to alkylate guanine N2. Footprinting analyses with DNase I and 1,10-phenanthroline-copper and exonuclease III digestions showed that ecteinascidin 743 covers three to five bases of DNA and exhibits a different sequence specificity than anthramycin in the Escherichia coli tyrosine tRNA promoter (tyrT DNA). The binding of ecteinascidin to DNA was abolished when guanines were substituted with inosines in this promoter. A band shift assay was designed to evaluate the influence of the bases flanking a centrally located guanine in an oligonucleotide containing inosines in place of guanines elsewhere. Ecteinascidin 743 and anthramycin showed similarities as well as differences in sequence selectivity. Ecteinascidin 743-guanine adducts appeared to require at least one flanking guanine and were strongest when the flanking guanine was 3' to the targeted guanine. These data indicate that ecteinascidin 743 is a novel DNA minor groove, guanine-specific alkylating agent.

Alkylation↗
PubMed1990

Lesion selectivity in blockage of lambda exonuclease by DNA damage.

Various kinds of DNA damage block the 3' to 5' exonuclease action of both E. coli exonuclease III and T4 DNA polymerase. This study shows that a variety of DNA damage likewise inhibits DNA digestion by lambda exonuclease, a 5' to 3' exonuclease. The processive degradation of DNA by the enzyme is blocked if the substrate DNA is treated with ultraviolet irradiation, anthramycin, distamycin, or benzo[a]-pyrene diol epoxide. Furthermore, as with the 3' to 5' exonucleases, the enzyme stops at discrete sites which are different for different DNA damaging agents. On the other hand, digestion of treated DNA by lambda exonuclease is only transiently inhibited at guanine residues alkylated with the acridine mustard ICR-170. The enzyme does not bypass benzo[a]-pyrene diol epoxide or anthramycin lesions even after extensive incubation. While both benzo[a]-pyrene diol epoxide and ICR-170 alkylate the guanine N-7 position, only benzo[a]-pyrene diol epoxide also reacts with the guanine N-2 position in the minor groove of DNA. Anthramycin and distamycin bind exclusively to sites in the minor groove of DNA. Thus lambda exonuclease may be particularly sensitive to obstructions in the minor groove of DNA; alternatively, the enzyme may be blocked by some local helix distortion caused by these adducts, but not by alkylation at guanine N-7 sites.

Aminoacridines↗
PubMed1995

Design of B-DNA cross-linking and sequence-reading molecules.

We report the design of hybrid molecules to bind in the minor groove of B-DNA, which combine DNA alkylating and cross-linking ability for increased chemotherapeutic efficacy, with sequence specificity, to minimize side effects. Optimal linkage geometries have been determined for the synthesis of bis-anthramycin and anthramycin-netropsin hybrid molecules. Earlier studies on linked drugs have typically been based on molecular mechanics calculations. This work, in contrast, uses the observed crystal structures of a netropsin/DNA complex and a new anthramycin/DNA complex to determine the exact spacing between two individual drugs when bound in the minor groove of B-DNA. Molecular linkers then are designed and tested between these two experimental positions, to form a chimeric or bis-linked compound molecule. A linked anthramycin-netropsin molecule has been designed specifically to target the polypurine tract second-strand primer site of the reverse transcriptase of HIV-1.

Base Sequence↗
PubMed1983

Acute treatment with pyrrolo(1,4)benzodiazepine antitumor antibiotics alters in vitro hepatic drug metabolizing activity in rats.

The pyrrolo(1,4)benzodiazepine antitumor antibiotic, anthramycin, shares a number of toxicities with the widely used anticancer agent adriamycin. We investigated whether acute doses of anthramycin and the structurally related compounds, sibiromycin and tomaymycin, would depress P-450-dependent drug biotransformations as has been reported for adriamycin. Alterations in drug metabolism rates were determined in rats using 50 and 75% of the approximate 7-day LD50 determined in mice. 4 days post dosing ethylmorphine demethylase and aniline hydroxylase activities in liver 9000 g supernatant were depressed from 26 to 76%. Tomaymycin lowered drug metabolism in a dose-related manner, while sibiromycin produced the greatest amount of depression. Like adriamycin, the pyrrolo(1,4)benzodiazepines possess the ability to depress hepatic drug metabolism and therefore may affect the disposition of compounds with which they are co-administered.

Aminoglycosides↗