ChemInform Abstract: Unsaturated Epoxy-C-Glycosides. A New Class of Antitumor Compounds with DNA Cleavage Properties.

Type IIA topoisomerases resolve topological problems in DNA by making a double-stranded break in one DNA segment, passing another DNA duplex through this break, and then resealing the break. Drugs (such as the widely used fluoroquinolone antibacterials and anti-cancer compounds such as etoposide) that stabilize double-strandedly cleaved DNA complexes with type IIA topoisomerases are cytotoxic. In GlaxoSmithKline a new class of novel bacterial topoisomerase inhibitors (NBTIs) have been developed. A 2.1Å crystal structure of a complex of GSK299423 with DNA and S. aureus DNA gyrase showed how the NBTI inhibits the enzyme by interacting with both the DNA and the protein. A pocket occupied by the compound in the protein (at the dimer interface) is absent in the apo structure, while the pocket occupied by the compound in the DNA has been formed by the enzyme stretching and untwisting the DNA between the two active sites. The NBTI structure has trapped a pre-cleavage complex of the enzyme, before the four base-pair double stranded break has occurred, and the structure gives insights into the role of metal ions in the cleavage mechanism of type IIA topoisomerases. Stuctures suggest how relatively small movements at the active sites (for example an ~3Å movement of a magnesium ion) can cause the cleavage of phosphate ester bonds and are coupled to the large domain movements involved in the catalytic cycle of these conformationally flexible enzymes. The binding site for the NBTI is close to but distinct from those for fluoroquinolones. Structures shows how the fluoroquinolone interacts with both the protein and the DNA by binding a non-catalytic magnesium ion and four associated waters. This provides a structural explanation for both fluoroquinolone resistance mutations and SAR (structure-activity relationships). Mechanistic implications of recent structural studies will be discussed.

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ChemInform Abstract: A NEW CLASS OF ANTITUMOR COMPOUNDS: 5′-NOR AND 5′,6′-SECO DERIVATIVES OF VINBLASTINE-TYPE ALKALOIDS

Chemischer Informationsdienst ◽

10.1002/chin.198011356 ◽

1980 ◽

Vol 11 (11) ◽

Author(s):

P. MANGENEY ◽

R. Z. ANDRIAMIALISOA ◽

N. LANGLOIS ◽

Y. LANGLOIS ◽

P. POTIER

Keyword(s):

New Class ◽

Antitumor Compounds ◽

Derivatives Of

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In Situ microscopy of the anodic etching of silicon

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100137537 ◽

1995 ◽

Vol 53 ◽

pp. 232-233

Author(s):

Frances M. Ross ◽

Peter C. Searson

Keyword(s):

Composite Structures ◽

High Surface ◽

High Surface Area ◽

Chemical Properties ◽

Selective Etching ◽

Silicon On Insulator ◽

Second Phase ◽

Porous Layers ◽

New Class ◽

Porous Semiconductors

Porous semiconductors represent a relatively new class of materials formed by the selective etching of a single or polycrystalline substrate. Although porous silicon has received considerable attention due to its novel optical properties1, porous layers can be formed in other semiconductors such as GaAs and GaP. These materials are characterised by very high surface area and by electrical, optical and chemical properties that may differ considerably from bulk. The properties depend on the pore morphology, which can be controlled by adjusting the processing conditions and the dopant concentration. A number of novel structures can be fabricated using selective etching. For example, self-supporting membranes can be made by growing pores through a wafer, films with modulated pore structure can be fabricated by varying the applied potential during growth, composite structures can be prepared by depositing a second phase into the pores and silicon-on-insulator structures can be formed by oxidising a buried porous layer. In all these applications the ability to grow nanostructures controllably is critical.

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