Biomedical subjects

B F McGuinness

Publications and source records attributed to B F McGuinness.

5 recordsLinked to original sources

PubMed1998

"High-load" polyethylene glycol-polystyrene (PEG-PS) graft supports for solid-phase synthesis.

The choice of a polymeric support is a key factor for the success of solid-phase methods for syntheses of organic compounds and biomolecules such as peptides and oligonucleotides. Classical Merrifield solid-phase peptide synthesis (SPPS), performed on low cross-linked hydrophobic polystyrene (PS) beads, sometimes suffers from sequence-dependent coupling difficulties. The concept of incorporating polyethylene glycol (PEG) into supports for solid-phase synthesis represents a successful approach to alleviating such problems. Previous reports from our laboratories have shown the advantages of "low-load" PEG-PS (0.15-0.25 mmol/g) for SPPS. Herein, we demonstrate that the beneficial aspects of the PEG-PS concept can be extended with resins that have higher loadings (0.3-0.5 mmol/g).

Amino Acid Sequence↗

PubMed1996

Amyloid probes based on Congo Red distinguish between fibrils comprising different peptides.

BACKGROUND: Amyloid plaques, which characterize degenerating tissue in Alzheimer's disease (brain) and type II diabetes (pancreas), were first visualized by staining with the dye Congo Red (CR). The ability of CR to recognize amyloid fibrils comprising diverse proteins suggests that the binding site includes an unidentified structural feature common to all amyloid fibrils. We set out to design and synthesize analogs of CR that could distinguish between fibrils comprising different peptides. RESULTS: Relative affinities of several CR analogs for two model amyloid fibrils were measured and compared to that of CR. Amyloid fibrils comprising peptides based on the critical carboxyl terminus of the Alzheimer's disease amyloid protein beta1-42 (beta34-42) and the critical region of the type II diabetes pancreatic amyloid protein, IAPP (IAPP20-29) were tested. The ratio of affinities of each individual CR analog for the two amyloid fibrils varied considerably. Complexation of certain metal ions (Cu(II), Zn(II), Ni(II), Cd(II)) by a CR analog did not abolish its affinity for amyloid but changed the affinity ratio significantly. CONCLUSIONS: This study demonstrates that small organic and organometallic molecules are capable of detecting differences in amyloid fibril structure and/or amyloid protein sequence. Molecules of this type could have utility as neuropathological probes or imaging agents, since they are much easier to prepare and functionalize than antibodies and are specific for the fibrillar form of the amyloid proteins.

Amino Acid Sequence↗

PubMed1992

Isolation and structure of an intrastrand cross-link adduct of mitomycin C and DNA.

A new covalent mitomycin C-DNA adduct (4) was isolated from DNA exposed to reductively activated mitomycin C (MC) in vitro. The MC-treated DNA was hydrolyzed enzymatically under certain conditions, and the new adduct was isolated from the hydrolysate by HPLC. Its structure was determined by ultraviolet and circular dichroism spectroscopy and chemical and enzymatic transformations conducted on microscale. In the structure, a single 2" beta, 7"-diaminomitosene residue is linked bifunctionally to two guanines in the dinucleoside phosphate d(GpG). The guanines are linked at their N2 atoms to the C1" and C10" positions of the mitosene, respectively. A key to the structure was a finding that removal of the mitosene from the adduct by hot piperidine yielded d(GpG); another was that the adduct was slowly converted to the known interstrand cross-link adduct 3 by snake venom diesterase and alkaline phosphatase. Adduct 4 represents an intrastrand cross-link in DNA formed by MC. Of the two possible strand-polarity isomers of 4, 4a in which the mitosene 1"-position is linked to the 3'-guanine of d(GpG) is designated as the proper structure, on the basis of the mechanism of the cross-linking reaction. The same adduct 4 was isolated from poly(dG).poly(dC), synthetic oligonucleotides containing the GpG sequence, and Micrococcus luteus and calf thymus DNAs. The relative yields of interstrand and intrastrand cross-links (3 and 4) were determined under first-order kinetic conditions; an average 3.6-fold preference for the formation of 3 over that of 4 was observed. An explanation for this preference is proposed.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation↗

PubMed1991

Reductive alkylation of DNA by mitomycin A, a mitomycin with high redox potential.

The mitomycins are a group of antitumor antibiotics that covalently bind to DNA upon reductive activation. Mitomycin A (1b; MA) is more toxic than its clinically useful mitomycin C (1a; MC). The greater toxicity of mitomycin A has been previously attributed to its higher reduction potential. In this report, the DNA alkylation products of reductively activated MA were isolated and characterized by conversion to the known 7-amino mitosene-deoxyguanosine adducts. The three major adducts formed were identified as a monoadduct, N2-(2"beta-amino-7"-methoxymitosen-1"alpha-yl)- 2'-deoxyguanosine (5), a decarbamoyl monoadduct, N2-(2"beta-amino-10"-decarbamoyl-7"-methoxymitosen-1"alpha-y l)-2'- deoxyguanosine (6), and a bisadduct, N2-(2"beta-amino-10"-deoxyguanosin-N2-yl-7-methoxymitosen-1" alpha- yl)-2'-deoxyguanosine (7). Under all reductive activation conditions employed, MA selectively alkylated the 2-amino group of guanine in DNA, like MC. In addition, both MA and MC alkylated DNA and cross-linked oligonucleotides to a similar extent. However, variations in the reductive activation conditions (H2/PtO2, Na2S2O4, or enzymatic) affected the distribution of the three major MA adducts in a different manner than the distribution of MC adducts was affected. A mechanism is proposed wherein the 7-methoxy substituent of MA allows initial indiscriminate activation of either of the drugs' two electrophilic sites. While oxygen inhibited cross-linking by MC, similar aerobic conditions exhibited little influence on the cross-linking ability of MA. Hence, the greater toxicity of MA may be influenced by increased and nonselective activation and cross-link formation in both aerobic and anaerobic cells. This effect is a direct consequence of the higher redox potential of MA as compared to MC.

Alkylation↗

PubMed1979

[Not Available].

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History, Modern 1601-↗