ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00521.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00522.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractOestrone 3‐O‐sulphamate, wherein a sulphamate moiety is a sulphate group surrogate relative to oestrone sulphate, is the most potent oestrone sulphatase inhibitor developed to date and inhibits oestrone sulphatase in a time‐ and concentration‐dependent manner, showing that it is acting as an active site‐directed irreversible inhibitor. It also inhibits dehydroepiandrosterone sulphatase, the enzyme which regulates the synthesis of androstenediol. Oestrone 3‐O‐sulphamate has also been shown to inhibit these enzymes in‐vivo. We report here its crystal structure and the synthesis and inhibitory activites of analogues in which the 3‐O atom is replaced by other heteroatoms (N and S).Oestrone 3‐N‐sulphamate and oestrone 3‐S‐sulphamate were found to inhibit placental microsome oestrone sulphatase weakly, i.e. 53% and 12%, respectively, at 50 μM (compared with>99% for oestrone 3‐O‐sulphamate), but none of these compounds appears to behave

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00523.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractOestrone sulphatase is a key enzyme involved in oestrogen synthesis in breast tumours in postmenopausal women. As breast tumours can be endocrine‐dependent, it is therefore feasible that blockage of this enzyme may be of value in the treatment of such tumours. Oestrone 3‐O‐sulphamate (EMATE) is the most potent inhibitor of oestrone sulphatase activity described to date. Here, we describe a preliminary examination of its physicochemical properties and the development of a self‐emulsifying formulation for potential administration of EMATE by the oral route. A preliminary assessment of the absorption of the drug from the gut was undertaken, and pharmacological activity, determined as oestrone sulphatase inhibition, was studied following intravenous and oral administration. A high‐performance liquid chromatography (HPLC) assay was developed to measure degradation of EMATE in the formulation and also its concentration in rat plasma.The drug was susceptible to degradation, but its stability in the formulation was satisfactory when stored at either 4°C or room‐temperature over the timespan required for a clinical trial. Plasma EMATE concentrations after 2 h were a function of the dose of drug administered orally to rats over the 10–40 mg kg−1range. After oral administration in the self‐emulsifying system, EMATE appeared to be rapidly absorbed, with the peak plasma concentration being detected at 30 min, after which plasma concentrations rapidly decreased. After intravenous administration, a similar plasma EMATE concentration was detected at 1 h to that observed after oral administration. Rat liver sulphatase activity was almost completely inhibited (>99%) within 30 min of oral or intravenous admin

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00524.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractOestrogen‐dependent breast cancers are considered to produce oestradiol in the breast through the initial action of a sulphatase on the oestrone sulphate reservoir, followed by reduction of the oestrone formed by a 17β‐hydroxysteroid dehydrogenase. The low rate of incidence of the disease in the Far East has been related to a high dietary intake of soya products containing flavones and isoflavones.We have found that the flavones chrysin (IC50 60‐5 μM), apigenin (18‐3 μM) and naringenin (19‐9 μM), and the isoflavones genistein (195 μM), biochanin A (47‐6 μM) and daidzein are potent inhibitors of human placental 17 β‐hydroxy s

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00525.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractTo develop new cytotoxins, which could find use as anti‐cancer agents, polyamine conjugates were synthesized containing spermine and an anthracene or acridine unit. Spermine is known to groove‐bind to DNA; anthracene and acridine are known to intercalate. It was hoped that these polyamine‐polyaromatic conjugates would use both modes of binding.Studies of growth inhibition of B16 murine melanoma cells showed the conjuates to be more effective than either spermine, anthracene‐9‐carboxylic acid or acridine‐9‐carboxylic acid, and of the conjugates, the acridine derivative showed grea

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00526.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe important anti‐cancer agent cyclophosphamide and its derivatives have been subjected to 22 crystal structure determinations, 19 of which are unique, revealing 24 independent molecules. These crystal structures show a general preference for chair conformations of the six‐membered ring but unexpected occurrence of boat and half‐chair forms, placement of the exocyclic oxygen atom that is more often axial than equatorial, flattening at the nitrogen atom of the oxazaphosphorinane ring, and a preference for antiperiplanar NCCC1 torsion angles in theN‐chloroethyl groups. Calculations are reported here that demonstrate the suitability of semi‐empirical molecular orbital methods for these systems and evaluate the energy and geometry of the molecules after optimization.Optimization of geometry with the semi‐empirical molecular orbital program, MOPAC, yielded torsion angles and ring puckering generally closer to the crystal structure and the result of ab‐initio optimization when the PM3 Hamiltonian was employed rather than AMI. However, AMI generally predicted an axial disposition of the exocyclic P = O bond, as found in the majority of crystal structures, while PM3 did not. The chair conformation of the ring is preferred, but boat and half‐chair forms are only 1–3 kcal mol−1higher in energy, as are alternative arrangements of the exocyclic P = O bond. Dipole moments usually increase when this bond is made equatorial; thus interaction with a polar solvent could mitigate the energy disadvantage o

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00527.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractA new strategy for automated solid phase synthesis of an oligonucleotide conjugate of the base sensitive anti‐cancer agent mitozolomide is described. Fully protected oligonucleotides were selected as base sensitive model sequences and were synthesized in 99% overall yields using a novel silyl‐linked controlled‐pore glass (SLCPG) solid support. Quantitative cleavage of compounds from SLCPG was achieved within 60 s at room temperature using tetra‐n‐butylammonium fluoride (TBAF) buffered with acetic acid. Reversed‐phase HPLC analysis of lipophilic compounds 5 and 8 showed distributions of diastereoisomers due to chirality at the protected phosphorus centres.Pentyl‐linked mitozolomide phosphoramidite, prepared in three steps from mitozolomide in 35% overall yield, was used in solid phase synthesis of a mitozolomide‐oligonucleotide conjugate. Cleavage of the conjugate from SLCPG and concomitant removal of the cyanoethyl groups from phosphorus was achieved within 2 h at 50°C using TBAF buffered

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00528.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe interaction between glutathione and the DNA‐binding pyrrolobenzodiazepine (PBD) antitumour antibiotic anthramycin has been studied.A polar adduct has been shown to form as a result of nucleophilic attack of the thiol group of glutathione on the electrophilic C11‐position of the PBD. The kinetics of formation of the adduct have been studied by HPLC and NMR, and its structure has been confirmed by isolation through preparative HPLC, followed by1H NMR and mass spectral analysis.These results suggest a possible role for glutathione conjugation during the metabolism of PBDs such as anthramy

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00529.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractTwo novel series of inhibitors of the DNA repair enzyme poly(ADP‐ribose)polymerase (PARP) were synthesized and evaluated for biological activity. In the benzimidazole‐4‐carboxamide series, the carbamoyl function was restricted into the putative biologically active conformation via an intramolecular hydrogen bond, while for quinazolin‐4‐[3H]‐ones this was achieved by incorporation of the group into a heterocyclic ring. For both series of compounds, syntheses involved acylation of substituted anthranilic acid derivatives, followed by acid‐ or base‐catalysed cyclization. 8‐Hydroxyquinazolin‐4‐[3H]‐ones were prepared from the corresponding 8‐methoxy compounds by dealkylation with boron tribromide.PARP inhibitory activity was determined in permeabilized L1210 murine leukaemia cells, in comparison with the established inhibitor 3‐hydroxybenzamide (IC50 = 8‐3 um). For both series, inhibitory activity varied with the nature of the 2‐substituent, with benzimidazole‐4‐carboxamides proving approximately tenfold more potent than the previously prepared benzoxazole‐4‐carboxamides. 2‐Arylbenzimidazoles were especially active, and 2‐(4‐methoxyphenyl)benzimidazole‐4‐carboxamide (IC50 = 60 nM) is the most potent PARP inhibitor reported to date. In the quinazolinone series, a 2‐(4‐nitrophenyl) substituent, and either an 8‐methyl or 8‐hydroxy group conferred potent inhibitory activity, with IC50

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00530.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY