PubMed Health⌕ Search

Biomedical subjects

F T Boyle

Publications and source records attributed to F T Boyle.

31 records · Page 2Linked to original sources
PubMed1993

The in vivo metabolic stability of dipeptide analogues of the quinazoline antifolate, ICI 198583, in mice.

In the search for quinazoline thymidylate synthase inhibitors that are not subject to intracellular polyglutamation, a class of dipeptide analogues of the diglutamate of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583-gamma-L-glu) has been evaluated for their stability to in vivo hydrolysis. Replacement of the second glutamate with another amino acid, e.g. alanine, prevented polyglutamation in vitro but such compounds were subject to hydrolysis when injected into mice. The extent of hydrolysis was measured in plasma, liver and kidney by HPLC analysis of tissue removed from mice 1 hr after i.p. injection. The enzyme responsible for this hydrolysis is thought to be a gamma-glutamyl hydrolase which hydrolyses the amide bond, releasing ICI 198583 which may then be polyglutamated. Development of stable dipeptide compounds was achieved by structural modification in two principal ways: either by replacement of the second amino acid (e.g. glutamate or alanine) with its D-enantiomer or removal of the carboxyl on the alpha-carbon of the second amino acid (alpha'-COOH). In this second approach two series of compounds were investigated. Monocarboxylate-derived dipeptides, e.g. ICI 198583-gamma-L-phenylalanine or ICI 198583-gamma-phenylglycine, resulted in stable compounds after removal of the alpha'-COOH (to give -ethylamide and -benzylamide derivatives, respectively). However, for the dicarboxylic amino acids a less clear picture emerged. Although removal of the alpha'-COOH from ICI198583-gamma-L-glutamate to give ICI 198583-gamma-gamma-aminobutyric acid resulted in a stable compound, the corresponding aspartate analogue (-beta-alanine) was subject to hydrolysis.

Animals↗
PubMed1993

The role of the reduced-folate carrier and metabolism to intracellular polyglutamates for the activity of ICI D1694.

The uptake of ICI D1694 into L1210 cells is very rapid and evidence strongly suggests that transport is via the reduced-folate/MTX cell membrane carrier (RFC); for example a cell line with a greatly impaired RFC is highly resistant to ICI D1694. Polyglutamates can be found intracellularly within a few minutes, so that experiments initially designed to measure transport were actually measuring transport and polyglutamation. After 30mins, in normal serum-containing tissue culture medium, the concentration of polyglutamates (di, tri and tetra) exceeded that of the parent drug 6-fold. Studies where cells were resuspended in drug-free medium demonstrated that the parent drug and its diglutamate could readily leave the cell. Folinic acid could markedly decrease the polyglutamation of ICI D1694, but had to be given simultaneously with the drug as a 4hr delayed rescue was less effective because substantial polyglutamation had already occurred. This effect was translated into considerable antagonism for cell growth inhibition by simultaneous folinic acid. The importance of the metabolism of ICI D1694 to polyglutamates to its potent cytotoxic activity is demonstrated by compounds related in structure to ICI D1694 but with different properties for the RFC and FPGS. For example, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolate (ICI 198583) owes its less potent cytotoxic activity to its poorer FPGS substrate activity (Km 40 microM compared with 1.3 microM for ICI D1694). Replacing the 2-methyl of either compound with amino, which appears to prevent use of the RFC, has a deleterious effect on growth inhibitory activity presumably by limiting the transport of the parent compounds into the cells, thereby slowing the rate of polyglutamate formation. Again a single change to another part of the molecule, that is methylation of the 7-position can have serious consequences on cytotoxic potency, particularly for the ICI D1694 molecule. The 7-methylated compounds are apparently poor or non-substrates for FPGS and therefore retain activity against a cell line unable to polyglutamate antifolates. These same compounds are only slightly affected by coincubation with folinic acid in L1210 tissue culture, consistent with the failure of these compounds to form intracellular polyglutamates. The results of short-exposure assays and in situ TS assays confirms that 7-methylation largely prevents the formation of a retained drug-form (polyglutamates), continuous exposure being necessary to maintain TS inhibition and cause a cytotoxic effect after removal of extracellular drug.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Synthesis and structure-activity relationships of a novel antifungal agent, ICI 195,739.

Antifungal azole derivatives are known to have potential for inhibition of host P-450 systems, and, in the attempts to increase the antifungal specificity of the inhibitor by identification of extra receptor binding within the enzyme complex, initial synthesis was guided by the structural requirements of the natural lanosterol substrate. With the aid of computer graphics, the 3'-styryl functionality was identified as a key structural element. For metabolically stable systems, in vitro-in vivo correlations exist, but optimizing oral activity resulted in the production of compounds with unacceptably long elimination half-lives. A disconnection of this relationship was achieved in pairs of structural isosteres with metabolic nonequivalence (CN:CONH2/OCH3:OCF3) and led to the identification of ICI 195,739, a novel 3'-tetrafluoropropoxystyryl-substituted bistriazole tertiary alcohol, as the compound of choice.

Animals↗
PubMed1982

Properties of a novel series of inhibitors of rumen methanogenesis; in vitro and in vivo experiments including growth trials on 2,4-bis (trichloromethyl)-benzo [1, 3]dioxin-6-carboxylic acid.

1. A procedure for measuring methane production by rumen contents incubated anaerobically in vitro is described. Assessments of methane production in vivo, in both sheep and cattle, were made by withdrawal of rumen contents and measuring their capacity to produce methane in vitro. 2. Many members of a series of 6-substituted 2,4-bis (trichloromethyl)-benzo[1,3]dioxins were potent inhibitors of methanogenesis by rumen contents in vitro. The most potent compound inhibited methane production by 70% or more at a concentration of 1 microgram/ml (approximately 2.5 mumol/l). 3. Two compounds, namely the 6-carboxylic acid (ICI 13409) and the 6-carboxamide (ICI 43586), caused a large inhibition of methanogenesis sustained for many hours, following a single intrarumen injection in sheep or cattle. Inhibition was maintained for long periods by single daily dosing directly into the rumen or by dietary administration. 4. In a 28-week growth trial in beef cattle inclusion of ICI 13409 in the concentrate element of the diet, at a level of 6 mg/kg body-weight, improved live-weight gain by 8.0% (P less than 0.05) with respect to untreated animals whilst reducing food intake by 5.0% (P less than 0.05). Smaller and not statistically-significant effects were seen with this compound at 3 mg/kg body-weight and with the antibiotic monensin (Romensin; Elanco PLC). All treatments significantly improved the retention of dietary energy into the carcass, offal and intestinal tracts of the trial animals and significantly reduced the quantity of methane eructed into expired gases.

Animals↗
PubMedDate not supplied

Antitumor effects of an antibody-carboxypeptidase G2 conjugate in combination with a benzoic acid mustard prodrug.

The F(ab')2 fragment of the antitumor monoclonal antibody, A5B7, was covalently linked to the bacterial enzyme carboxypeptidase G2 (CPG2). The resulting conjugate was used in combination with a prodrug of a benzoic acid mustard alkylating agent to treat human colon tumor xenografts in a two-step targeting strategy, antibody-directed enzyme prodrug therapy (ADEPT). The prodrug, 4-[(2-chloroethyl) (2-mesyloxyethyl)amino]-benzoyl-L-glutamic acid is rapidly converted by CPG2 to a drug that is at least 15x more toxic in vitro against LS174T colorectal tumor cells than the prodrug. Optimal tumor/blood ratios of the A5B7-CPG2 were achieved 72 h after administration of the conjugate to athymic mice bearing established LS174T tumor xenografts. Significant antitumor activity was seen in LS174T tumor-bearing mice treated with the conjugate followed 3 d later by the prodrug. In contrast, prodrug, conjugate, or active drug alone did not result in any antitumor activity in this tumor model. These studies demonstrate the advantage of a two-step ADEPT system for the treatment of colorectal cancer.

Animals↗
PubMedDate not supplied

ZD1694 (Tomudex): a new thymidylate synthase inhibitor with activity in colorectal cancer.

ZD1694 (Tomudex) is a new antifolate which is a specific inhibitor of thymidylate synthase (TS). Evidence suggests that ZD1694 has a spectrum of activity that only partially overlaps with 5-fluorouracil (modulated with leucovorin) against colon tumours in vitro. Potent cytotoxic activity is dependent upon active uptake into cells via the reduced folate/methotrexate cell membrane carrier (RFC) and subsequent metabolism to polyglutamated forms (tri, tetra and pentaglutamates). These polyglutamates are approximately 60-fold more active as TS inhibitors and are not effluxed readily from cells. Extensive polyglutamation also occurs in various mouse tissues (e.g. small intestinal epithelium, liver and kidney), resulting in high tissue/plasma drug ratios which persist for a prolonged period. ZD1694 has antitumour activity in mice, although the high plasma thymidine in this species complicates: (1) the interpretation of therapeutic index; (2) tumour types in which activity is likely to be observed; and (3) translation of doses and schedules for clinical evaluation. ZD1694 entered clinical study and has completed Phase I and II evaluation, with activity observed in several tumour types. Appreciable activity in the Phase II colorectal study (29% objective response rate on interim analysis) led to the current Phase III study, randomised against 5-fluorouracil/leucovorin.

Animals↗
PubMedDate not supplied

Antifungal antibiotics from Calcarisporium thermophilum: a new source of 15-azahomosterol derivatives.

Two antifungal metabolites isolated from Calcarisporium thermophilum were identified as 15-azahomosterols related to the compounds previously isolated from Geotrichum flavo-brunneum. By full spectral comparison with authentic 15-aza-24-methylene-D-homocholesta-8,14-dien-3 beta-ol (A 25822 B) from G. flavo-brunneum, the Calcarisporium metabolites were characterized as the 4 alpha-methyl- and 4,4-dimethyl-analogues of A 25822 B. Several minor members of the series were also detected, and tentatively identified by MS analysis. The 15-azahomosterols exhibited good antifungal activity towards Candida parapsiliosis, though the activities were somewhat lower than that of the 4-demethyl derivative A25822 B. Calcarisporium thermophilum is the second microorganism known to synthesize these unusual 15-azahomosterol derivatives.

Antifungal Agents↗