Laurence Hurley

PMID: 328469;Abstract:

The pyrrolo(1,4)benzodiazepine antibiotics comprise the antibiotics, anthramycin, tomaymycin, sibiromycin, dextrochrysin and the neothramycins A and B. Structure activity relationships indicate that in addition to a pyrrolo(1,4)benzodiazepine nucleus, these compounds also require a 10,11 carbinolamine and an unsaturated side chain at C-2 to retain their potent biological activities. The antibiotics within this group show antiviral and most significantly antitumor activity. Anthramycin and sibiromycin have been shown to have a wide range of antitumor activity in animal models, and in the case of anthramycin, activity against both solid and liquid tumors in man. Tryptophan, methionine and tyrosine supply the biosynthetic building blocks for anthramycin, tomaymycin and the aglycone moiety of sibiromycin. Parallel pathways from tryptophan, via kynurenine lead to the anthranilate moieties of these three antibiotics. Conversion of tyrosin, via dopa, to the C2 and C3-proline moieties of anthramycin, tomaymycin and sibiromycin involves meta cleavage of the aromatic ring of a tyrosine metabolite and loss of two aromatic carbon atoms. Addition of the pyrrolo(1,4)benzodiazepine antibiotics to bacterial or mammalian cells leads to a potent inhibition of RNA and DNA synthesis, while protein synthesis is virtually unaffected at these same antibiotic concentrations. Overwhelming evidence suggests that the pyrrolo(1,4)benzodiazepine antibiotics form a covalent linkage with DNA. No major modification of the pyrrolo(1,4)benzodiazepine antibiotics occurs upon reaction with DNA, and intact antibiotic can be released from their respective DNA adducts under certain acidic conditions. Structure activity relationships lead to the conclusion that the DNA reactive site on the pyrrolo(1,4)benzodiazepine antibiotics is the 10,11-carbinolamine. Most likely the covalent linkage with DNA involves a nucleophilic attack originating from a basic group on DNA at C-11 of the antibiotics resulting in loss of the conjugate acid.

PMID: 6928034;Abstract:

Pretreatment of Swiss Webster mice with coenzyme Q10 (CoQ) markedly reduced the lethality of the antitumor antibiotic anthramycin as well as its ability to decrease ventricular weights. In tumor-bearing mice CoQ pretreatment did not produce any consistent alteration of radioactivity levels in blood, heart, tumor, lungs, kidneys, liver, muscles, brain, or spleen after [15-³H]anthramycin administration. Gross alterations in anthramycin distribution is probably not the mechanism by which CoQ alters the cardiotoxicity and lethality of anthramycin.

PMID: 8718873;Abstract:

Integration Host Factor (IHF) is a sequence-specific DNA-bending protein that is proposed to interact with DNA primarily through the minor groove. We have used various chemical probes [(+)-CC-1065, a minor-groove-specific agent that alkylates N3 of adenine and traps bends into the minor groove; pluramycin, a minor-major-groove threading intercalator that alkylates N7 of guanine; KMnO 4, which reacts more strongly with bases in denatured DNA] to gain more information on the interaction of IHF with the H' site of phage λ. In addition to the 13-bp core consensus recognition element present at all IHF binding sites, the H' site also has an upstream AT-rich element that increases the affinity of IHF for this site. Our results reveal new details of IHF-DNA interaction at this site. Results with (+)-CC-1065 modification suggest that IHF interacts with the adenines on the 3'-side of the AT-rich element and likely induces a minor-groove bend in its vicinity, which in turn stabilizes the interaction. Pluramycin modification experiments suggest the presence of both short- and long-range structural perturbations (possible DNA unwinding events) on either side of the IHF contact region. Although IHF is known to induce a large bend in DNA at the H' site, no separation of base pairs was detected when the bent DNA was probed with KMnO 4. DNA cyclization studies indicate a large magnitude (approximately 180°) for the IHF-induced bend at the H' site, consistent with > 140° bend estimated by gel electrophoresis methods. These studies suggest that IHF-induced DNA bending is accompanied by the introduction of a DNA node, DNA unwinding, and/or by some other DNA distortion. An enhanced binding and stability of IHF was observed on small circular DNA.